Host targeted inhibitors of dengue virus and other viruses

ABSTRACT

Novel antiviral compounds of Formulae (I)-(III) are provided: 
     
       
         
         
             
             
         
       
     
     The inventive compounds, pharmaceutical compositions thereof, and kits including the inventive compounds are useful for the prevention and treatment of infectious diseases caused by viruses, for example, by Flaviviridae virus (e.g., Dengue virus (DENV)), Kunjin virus, Japanese encephalitis virus, vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), human cytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus, Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equine encephalitis virus (VEEV), or Rift Valley Fever virus (RVFV).

RELATED APPLICATIONS

The present invention is a continuation of and claims priority under 35U.S.C. § 120 to U.S. application, U.S. Ser. No. 14/391,638, filed Oct.9, 2014, which is a national stage filing under 35 U.S.C. § 371 ofinternational PCT application, PCT/US2013/032488, filed Mar. 15, 2013,which claims priority under 35 U.S.C. § 119(e) to U.S. provisionalapplication, U.S. Ser. No. 61/622,828, filed Apr. 11, 2012, each ofwhich is incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant numbersHG006097, R01 AI076442, U54 CA156732-01, and U54 AI057159 awarded by theNational Institutes of Health. The government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

Dengue virus (DENV) is one of the most significant mosquito-borne viralinfections affecting humans today and is an NIAID (National Institute ofAllergy and Infectious Diseases) Category A Biodefense pathogen. DENV isa plus-stranded RNA virus and a member of the Flaviviridae family. Thefour Dengue virus serotypes (DENV1, DENV2, DENV3, and DENV4) are definedby the viral envelope protein (E) and share 60% sequence homology at theamino acid level. Due to the large number of people at risk forinfection, DENV is the most widespread mosquito-borne virus affectinghumans today. An estimated 2.5 billion people live in areas at risk forepidemic transmission, and an estimated 100 million people are infectedwith DENV annually. Infection with DENV is responsible for diseasesranging from Dengue fever to the much more severe and life-threateningDengue hemorrhagic fever (DHF) and Dengue shock syndrome (DSS) that arecharacterized by vascular leakage. An estimated 500,000 cases of DHF andDSS occur annually and are associated with 2.5% fatality althoughfatality rates for DHF and DSS can exceed 20% if untreated (Dengue andDengue haemorrhagic fever. Vol. 2010 (WHO Media Centre, 2010)).

The determinants of disease severity for DENV infection and thepathogenesis mechanisms underlying DHF and DSS are poorly understood.Vascular leakage, which is the hallmark of DHF, is largely believed tobe caused by a host-mounted “cytokine storm” but is correlated with highlevels of viremia, particularly early in infection (Halstead, Science(1988) 239:476-481; Gubler, Dengue and Dengue Hemorrhagic Fever; Gupleet al., ed.; CAB International: New York, 1997; Vol. 1; pp. 1-22; Vaughnet al., J. Infect. Dis. (2000) 181:2-9; Libraty et al., J. Infect. Dis.(2002) 185:1213-1221; Wang et al., Virology (2003) 305:330-338; and Endyet al., J. Infect. Dis. (2004) 189:990-1000). In vivo data havesuggested that therapies that lower Dengue viral burden can amelioratethe inflammatory “cytokine storm” associated with DHF or DSS.

The strong correlation between viral load and disease severity suggeststhat antivirals that inhibit DENV and reduce viral burden might reducethe severity of DENV-associated disease. Peak virus titers on the orderof 10⁷ to 10⁸ MID₅₀/mL (median infectious dose/mL plasma) were found inpatients with Dengue fever; patients with DHF or DSS exhibited titers100-fold and 1000-fold higher, respectively (Vaughn et al., J. Infect.Dis. (2000) 181:2-9; and Libraty et al., J. Infect. Dis. (2002)185:1213-1221). Additional studies of viremia and estimated infectedcell mass confirm this (Libraty et al., J. Infect. Dis. (2002)185:1213-1221; Wang et al., Virology (2003) 305:330-338; Libraty et al.,J. Infect. Dis. (2002) 186:1165-1168; Wang et al., Clin. Infect. Dis.(2006) 43:1023-1030; and Halstead, Dengue. Lancet (2007) 370:1644-1652).Recent experimental support for the potential efficacy of anti-DENVtherapeutics includes the demonstration that reduction of virus titersby 70-93% was associated with a reduction in serum levels ofinflammatory cytokines (i.e., IL6, TNFα, IL12p70, and MCP-1) in a mousemodel of Dengue fever (Schul et al., J. Infect. Dis. (2007)195:665-674). These effects were observed with 7-DMA, a compound withmodest activity against the DENV RNA-dependent polymerase (EC₅₀ 15 μM)(Wu et al., J. Virology (2002) 76:3596-3604).

Despite the spread of the four DENV serotypes worldwide and theincreasing incidence of DHF and DSS over the past fifty years, therecurrently are no specific therapeutics to combat DENV infection or avaccine that protects against all four DENV serotypes. It remains anopen question whether immunization directed towards a limited set ofepitopes conserved across all DENV serotypes can elicit tetravalentprotective immunity or if a successful vaccine will require fourdistinct type-specific responses. Further complicating DENV vaccinedevelopment is the potential for non-neutralizing antibody responses toenhance the infection of immune cells and to exacerbate the disease dueto the interaction of the antibody Fc region with activating Fcγreceptors (FcγR) on immune cells, a phenomenon known asantibody-dependent enhancement of infection (ADE). Currently, the onlytreatment for DHF or DSS is supportive care primarily maintaining thepatient's circulating fluid volume. Thus, while continuing efforts todevelop a protective tetravalent vaccine are imperative, alternativestrategies to prevent and control DENV infection are also urgentlyneeded.

SUMMARY OF THE INVENTION

Antiviral agents that act via a host target may have higher barriers toresistance and broader inhibitory activity against multiple viralpathogens, compared with antivirals that act via a viral target. Novelcompounds are provided that show efficacy against Flaviviridae viruses(e.g., all four Dengue serotypes (DENV1, DENV2, DENV3, and DENV4)),Kunjin virus, Japanese encephalitis virus, vesicular stomatitis virus,Junin virus, Ebola virus, Marburg virus (MARV), Lassa fever virus(LASV), Venezuelan equine encephalitis virus (VEEV), Rift Valley Fevervirus (RVFV), and other viruses. Without wishing to be bound by aparticular theory, these compounds are thought to covalently modifycysteine residues of a host target. These compounds suggest a newparadigm for developing broad-based antiviral agents.

The present invention provides compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,prodrugs, and compositions thereof. The present invention furtherprovides methods of using the inventive compounds, and pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, co-crystals,tautomers, stereoisomers, isotopically labeled derivatives, prodrugs,and compositions thereof, to study the inhibition of viruses, to treator prevent infectious diseases caused by viruses, to reduce viral loadin a subject, and to screen a compound library to identify compoundsthat prevent or inhibit entry of viruses into host cells. Also providedare kits, containing one or more inventive compounds, or compositionsthereof, for treating or preventing infectious diseases.

In one aspect, the present invention provides compounds of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof;wherein Ring A, Ring C, R^(A), R^(C), R^(D), L, k, and n are as definedherein.

In one aspect, the present invention provides compounds of Formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof;wherein Ring A, Ring C, R^(A), R^(C), R^(D), R^(j1), R^(j2), R^(j3), L,k, and n are as defined herein.

In one aspect, the present invention provides compounds of Formula(III):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof;wherein Ring A, Ring C, R^(A), R^(C), R^(D), R^(q), L, k, and n are asdefined herein.

Exemplary compounds of Formula (I) include, but are not limited to:

In another aspect, the present invention provides pharmaceuticalcompositions including a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, and optionally a pharmaceutically acceptable excipient.

In still another aspect, the invention provides methods for thetreatment of infectious diseases in a subject caused by viruses, methodsfor reducing viral load in a subject, and methods of preventing viralinfections in a subject who was or may be exposed to viruses. Theviruses, the infection of which may be treated or prevented by theinventive methods, include Flaviviridae viruses (e.g., Dengue virus(DENV), including Dengue virus 1 (DENV1), Dengue virus 2 (DENV2), Denguevirus 3 (DENV3), and Dengue virus 4 (DENV4); West Nile virus; tick-borneencephalitis virus; yellow fever virus; hepatitis C virus; hepatitis Gvirus; bovine viral diarrhea; classical swine fever virus; and hogcholera virus), Kunjin virus, Japanese encephalitis virus, vesicularstomatitis virus (VSV), vesicular stomatitis virus (VSV) pseudotypedwith rabies glycoprotein, vesicular stomatitis virus (VSV) pseudotypedwith Ebola glycoprotein, herpes simplex virus 1 (HSV-1), humancytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus, Marburgvirus (MARV), Lassa fever virus (LASV), Venezuelan equine encephalitisvirus (VEEV), and Rift Valley Fever virus (RVFV). The infectiousdiseases being treated or prevented by the inventive methods include,but are not limited to, dengue fever, dengue hemorrhagic fever, anddengue shock syndrome (DSS). The methods of the invention includeadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer,stereoisomer, isotopically labeled derivative, or prodrug thereof.

In yet another aspect, the present invention provides methods ofscreening a library of compounds to identify one or more compounds thatprevent or inhibit entry of a virus into a host cell. The methods ofscreening a library include providing at least two different compoundsof the invention, or pharmaceutically acceptable salts, solvates,hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, or prodrugs thereof; and performing atleast one assay using the different compounds of the invention, orpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,or prodrugs thereof, to detect entry of the virus into the host cell.

Another aspect of the present invention relates to uses of the inventivecompounds, and pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, prodrugs, and pharmaceutical compositions thereof, fortreating or preventing an infectious disease in a subject sufferingtherefrom.

In another aspect, the invention provides kits for treating orpreventing an infectious disease (e.g., a viral disease). The inventivekits include a first container containing a therapeutically effectiveamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, or prodrug thereof; and instructionsfor administering the compound to a subject to treat or prevent theinfectious disease. A kit may include multiple unit dosages, forexample, for multiple days of treatment.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Figures, the Examples, andthe Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers.” Stereoisomers that are not mirror images of one anotherare termed “diastereomers,” and those that are non-superimposable mirrorimages of each other are termed “enantiomers”. When a compound has anasymmetric center, for example, a carbon atom of the compound is bondedto four different groups, a pair of enantiomers is possible. Anenantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates planepolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture.” For example, the compounds described herein can be in the formof an individual enantiomer, diastereomer or geometric isomer, or can bein the form of a mixture of stereoisomers, including racemic mixturesand mixtures enriched in one or more stereoisomer. Isomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), n-propyl(C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄),isobutyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl (C₅), neopentyl(C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), and n-hexyl (C₆).Additional examples of alkyl groups include n-heptyl (C₇), n-octyl (C₈)and the like. Unless otherwise specified, each instance of an alkylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents. In certain embodiments, the alkyl group isunsubstituted C₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, thealkyl group is substituted C₁₋₁₀ alkyl.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

As used herein, a “hydrocarbon chain” refers to a substituted orunsubstituted divalent alkyl, alkenyl, or alkynyl group. A hydrocarbonchain includes at least one chain, each node (“carbon unit”) of whichincluding at least one carbon atom, between the two radicals of thehydrocarbon chain. For example, hydrocarbon chain—C^(A)H(C^(B)H₂C^(C)H₃)— includes only one carbon unit C^(A). The term“C_(x) hydrocarbon chain,” wherein x is a positive integer, refers to ahydrocarbon chain that includes x number of carbon unit(s) between thetwo radicals of the hydrocarbon chain. If there is more than onepossible value of x, the smallest possible value of x is used for thedefinition of the hydrocarbon chain. For example, —CH(C₂H₅)— is a C₁hydrocarbon chain, and

is a C₃ hydrocarbon chain. When a range of values is used, e.g., a C₁₋₆hydrocarbon chain, the meaning of the range is as described herein. Ahydrocarbon chain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chainmay also be unsaturated and include one or more C═C and/or C≡C bondsanywhere in the hydrocarbon chain. For instance, —CH═CH—(CH₂)₂—,—CH₂—C≡C—CH₂—, and —C≡C—CH═CH— are all examples of a unsubstituted andunsaturated hydrocarbon chain. In certain embodiments, the hydrocarbonchain is unsubstituted (e.g., —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments

are not within the scope of the hydrocarbon chains described herein. Incertain embodiments, the hydrocarbon chains is alkylene. In certainembodiments, the hydrocarbon chains is alkenylene. In certainembodiments, the hydrocarbon chains is alkynylene.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 nelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. A “partially unsaturated” ring system is furtherintended to encompass rings having multiple sites of unsaturation, butis not intended to include aromatic groups (e.g., aryl or heteroarylgroups) as herein defined. Likewise, “saturated” refers to a group thatdoes not contain a double or triple bond, i.e., contains all singlebonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, which are divalent bridging groups arefurther referred to using the suffix -ene, e.g., alkylene, alkenylene,alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R,—SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR, —OSO₂R^(aa), —S(═O)R^(aa),—OS(═O)R^(aa), —Si(R^(aa))₃, —OSi(R^(aa))₃—C(═S)N(R^(bb))₂,—C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa), —SC(═O)SR^(aa),—OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC(═O)R^(aa), —P(═O)₂R^(aa),—OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,—P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂,—OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂,—P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂,—B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc); each instance of R^(aa)is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa) groups arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups; each instance of R^(bb) is, independently, selectedfrom hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc)C)N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, —C(═S)NH(C₁₋₆ alkyl), —C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, F⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like). “Halo” or “halogen” refers to fluorine(fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine(iodo, —I).

“Acyl” as used herein refers to a moiety selected from the groupconsisting of —C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or—C(═S)SR^(aa), wherein R^(aa) and R^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substituents include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc), and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamante, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (t-butoxycarbonyl, BOC, or Boc),1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate(Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc),4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate,N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate(Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate,p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzylcarbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethylcarbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate,2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate(Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), P-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R)N(R^(bb)2, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(NR^(bb)N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa),—Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,t-butoxycarbonyl (BOC or Boc), (phenyldimethylsilyl)methoxymethyl(SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl,4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM),2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP),3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl,4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,4-methoxytetrahydrothiopyranyl S,S-dioxide,1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP),1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, a-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, a-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R″)₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

A “leaving group” is a molecular fragment that departs with a pair ofelectrons in heterolytic bond cleavage. As used herein, the term“leaving group” is given its ordinary meaning in the art of syntheticorganic chemistry and refers to an atom or a group capable of beingdisplaced by a nucleophile. Usually a leaving group is a substituentthat is present on a chemical compound that is capable of beingdisplaced by another group. Leaving groups can be anions or neutralmolecules. Examples of suitable leaving groups include, but are notlimited to, halides (such as fluoride, chloride, bromide, and iodide),esters, thioesters, phosphates, sulfates, sulfinates, sulfonates,alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. Insome cases, the leaving group is a sulfonic acid ester, such aspara-toluenesulfonate (“tosylate,”-OTs), methanesulfonate(“mesylate,”-OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), ortrifluoromethanesulfonate (“triflate,”-OTf). In some cases, the leavinggroup is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases,the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. Insome embodiments, the leaving group is a sulfonate-containing group. Insome embodiments, the leaving group is a tosylate group. The leavinggroup may also be a phosphineoxide (e.g., formed during a Mitsunobureaction) or an internal leaving group such as an epoxide or cyclicsulfate. Other non-limiting examples of leaving groups are water,ammonia, alcohols, ether moieties, thioether moieties, zinc halides,magnesium moieties, diazonium salts, copper moieties, and boron moieties(such as boronic acids and trihaloborate salts such as trifluoroboratesalts). These and other exemplary substituents are described in moredetail in the Detailed Description, Figures, Examples, and claims. Theinvention is not intended to be limited in any manner by the aboveexemplary listing of substituents.

Other Definitions

The following definitions are more general terms used throughout thepresent application:

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and arylsulfonate.

The term “polymorphs” means crystal structures in which a compound (or asalt, hydrate, or solvate thereof) can crystallize in different crystalpacking arrangements, all of which have the same elemental composition.Different crystal forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Crystallinepolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “co-crystal” refers to a crystalline structure composed of atleast two components, where the components may be atoms, ions, ormolecules. Typically, the components interact with one another to formthe crystalline structure through ionic or, more commonly, non-ionicinteractions. For a specific co-crystal form, all its components can befound within a single crystal lattice (unit cell) and are usually in adefinite stoichiometric ratio. A component of a co-crystal may be asolid or liquid when the component is in its pure form. Crystallinesalts, crystalline hydrates, and crystalline solvates are also withinthe meaning of co-crystals.

“Solvate” refers to forms of the compound that are associated with asolvent or water (also referred to as a “hydrate”), usually by asolvolysis reaction. This physical association includes hydrogenbonding. Conventional solvents include water, methanol, ethanol, aceticacid, DMSO, THF, diethyl ether, and the like. The compounds of theinvention may be prepared, e.g., in crystalline form, and may besolvated or hydrated. Suitable solvates include pharmaceuticallyacceptable solvates, such as hydrates, and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofthe crystalline solid. “Solvate” encompasses both solution-phase andisolable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

As used herein, “isotopically labeled derivatives” of a compound referto derivatives of the compound wherein at least one atom of the compoundis enriched for an isotope that is higher or lower in molecular weightthan the most abundant isotope of the atom found in nature.

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like. Other derivatives of the compounds of thisinvention have activity in both their acid and acid derivative forms,but in the acid sensitive form often offers advantages of solubility,tissue compatibility, or delayed release in the mammalian organism (see,Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985). Prodrugs include acid derivatives well know to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacid with a suitable alcohol, or amides prepared by reaction of theparent acid compound with a substituted or unsubstituted amine, or acidanhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters,amides and anhydrides derived from acidic groups pendant on thecompounds of this invention are particular prodrugs. In some cases it isdesirable to prepare double ester type prodrugs such as (acyloxy)alkylesters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the C₁ to C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, aryl, C₇-C₁₂ substituted aryl, andC₇-C₁₂ arylalkyl esters of the compounds of the invention.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs), fish, andbirds (e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female and at any stage of development. Anon-human animal may be a transgenic animal, such as a transgenic mouseor transgenic pig.

“Treat,” “treating,” and “treatment” contemplate an action that occurswhile a subject is suffering from a condition, e.g., an infectiousdisease caused by a virus, and that reduces the severity of thecondition or retards or slows the progression of the condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the condition and that inhibitsor reduces the severity of the condition (“prophylactic treatment”).

As used herein, “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound of the present invention refers toan amount sufficient to elicit the desired biological response, i.e.,treating the condition. As will be appreciated by those of ordinaryskill in this art, the effective amount of a compound of the inventionmay vary depending on such factors as the desired biological endpoint,the pharmacokinetics of the compound, the condition being treated, themode of administration, and the age and health of the subject. Aneffective amount encompasses therapeutic and prophylactic treatment.

A “therapeutically effective amount” of a compound of the presentinvention is an amount sufficient to provide a therapeutic benefit inthe treatment of a condition, e.g., an infectious disease caused by avirus, or to delay or minimize one or more symptoms associated with thecondition. A therapeutically effective amount of a compound means anamount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of the condition, or enhances the therapeutic efficacy of anothertherapeutic agent.

A “prophylactically effective amount” of a compound of the presentinvention is an amount sufficient to prevent a condition, e.g., aninfectious disease caused by a virus, or one or more symptoms associatedwith the condition or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of a therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the condition. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

A “host factor,” as used herein, refers to a biomolecule of a hostwherein the biomolecule contributes to a viral infection in the host. Anexample of the host factor is a membrane receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the chemical structures of certain selective kinaseinhibitors.

FIGS. 2A to 2G show the structures and anti-DENV activity of QL-XII-47and analogs used in the study. All infections were performed in Huh7cells at an MOI (multiplicity of infection) of 1. Illustrated in FIG. 2Aare the chemical structures of exemplary compounds. FIG. 2B includes adose response curve of QL-XII-47 in a viral yield reduction assaymeasured against DENV2 NGC (strain New Guinea C), in Huh7 cells. Shownin FIG. 2C is the inhibitory effect of the compounds in yield reductionassays. Compounds were present at 3 μM at 0-24 hours post-infection withDENV2 NGC. Viral yield at 24 hours was quantified by plaque formationassay. QL-XII-47's anti-DENV activity is not due to host cell toxicitysince no cytotoxicity is observed at 20 μM, the highest concentrationtested in a highly sensitive luminescent assay of cell viability (FIG.2D). QL-XII-47 exhibits potent activity against strains DENV1 WP74,DENV2 NGC, DENV3 THD3, and DENV4 TVP360 (FIG. 2E). 2 μM QL-XII-47 causesa greater than 10-fold reduction in Kunjin virus yield (FIG. 2F).Negative control compound QL-XI-76 exhibits minimal anti-DENV activityat concentrations up to 10 μM, the highest concentration tested (FIG.2G).

FIGS. 3A to 3E demonstrate that QL-XII-47 inhibits a step early in theDENV life cycle via a host target. All infections were with DENV2 NGC inHuh7 cells at an MOI of 1. (FIG. 3A) Preincubation of cells withQL-XII-47 for 6 hours prior to infection with DENV results in inhibitioncomparable to that observed when infected cells are treated withQL-XII-47 at 0-24 hours post-infection. (FIG. 3B) QL-XII-47 exhibitsmaximal anti-DENV activity when added 0-3 hours post-infection andbegins to lose anti-DENV activity when added at later time points. (FIG.3C) QL-XII-47 inhibits DENV in a single-cycle reporter virus assay(Ansarah-Sobrinho et al., Virology (2008) 381:67-74) that measuressuccessful entry and translation of the viral RNA. Negative controlQL-XI-76 does not inhibit DENV in this system. (FIG. 3D) QL-XII-47 doesnot inhibit gene expression or replication of a reporter replicon RNA5electroporated into Huh7 cells. (FIG. 3E) QL-XII-47 does not inhibitexpression or secretion of DENV virus-like particles (VLPs).

FIGS. 4A and 4B demonstrate that QL-XII-47 blocks a late step in DENVentry. Huh7 cells were infected with DENV2 NGC at an MOI of 1 for 1 hand then washed exhaustively to remove extracellular virus (FIG. 4A).Cells were lysed at various time points post-infection; intracellulargenomic DENV RNA and GAPDH mRNA were quantified by qRT-PCR assay. ADENV2-derived stem peptide was used as a control to block viral fusionduring entry. At 24 h post-infection, DENV genomic RNA is increasing dueto replication (shown in black), and the DENV RNA in thefusion-inhibited sample is decreasing due to degradation since the viruscannot escape the endosome (shown in blue). DENV genomic RNA in theQL-XII-47-treated sample is relatively unchanged (shown in red),suggesting that the nucleocapsid escapes the endosome but the viral RNAis protected from cytoplasmic nucleases. Huh7 cells were infected at anMOI of 10 and then stained at various times post-transfection by in situhybridization using a ViewRNA probe (Panomics) specific for a sequencein the 3′UTR of the DENV genome (FIG. 4B). The probe has been validatedto detect single copy RNA. In the presence of QL-XII-47, DENV RNApersists in a punctate localization pattern suggesting that it isprotected from cytoplasmic nucleases and that the viral entry process isblocked.

FIGS. 5A to 5V illustrate that QL-XII-47 and QL-XII-56 inhibit virusesoutside the Flaviviridae family. 2 μM QL-XII-47 inhibits infection ofBsc1 and Vero cells with VSV and VSV pseudotyped with rabies virusglycoprotein (RABV) and Ebola glycoprotein (EboV), as evidenced byimmunostaining for viral proteins (FIG. 5A). Inhibition is maximal whenQL-XII-47 is present before (−1 hpi) or at the time of infection (0hpi). Inhibition is lost when addition of QL-XII-47 is delayed to 1 (1hpi) or 3 hours post-infection (3 hpi). QL-XII-47 but not QL-XI-76inhibits: infection of human foreskin fibroblasts by a reporter HCMVthat expresses luciferase under the control of the UL97 promoter (FIG.5B); infection and plaque formation of HSV-1 in Vero cells (FIG. 5C);and poliovirus infection and viral gene expression in Vero cells (FIG.5D). QL-XII-47 also inhibits the cytopathic effects of JapaneseEncephalitis Virus (JEV) (FIG. 5E) and Junin virus (FIG. 5F). *indicates that no plaques were detected at 8 μM of QL-XII-47. **indicates that no plaques were detected at 8 μM of acyclovir and thatlower concentrations were not tested. Data in FIGS. 5A to 5V weregenerated in generous collaboration with S. Piccinotti and S. Whelan(VSV pseudotypes); H. Chen and D. Coen (HCMV and HSV-1); E. Sun and X.Zhuang (polio); and IBT Bioservices (JEV and Junin). FIGS. 5G to 5J showthe inhibitory activities of QL-XII-47 and QL-XII-56 against Ebolaglycoprotein (EBOV) at an MOI of 1 (FIGS. 5G and 5I) or 10 (FIGS. 5H and5J). FIGS. 5K to 5N show the inhibitory activities of QL-XII-47 andQL-XII-56 against Marburg virus (MARV) at an MOI of 1 (FIGS. 5K and 5M)or 10 (FIGS. 5L and 5N). FIGS. 5O and 5P show the inhibitory activitiesof QL-XII-47 and QL-XII-56 against Junin virus (JUNV) at an MOI of 1(FIG. 5O) or 10 (FIG. 5P). FIGS. 5Q and 5R show the inhibitoryactivities of QL-XII-47 and QL-XII-56 against Lassa fever virus (LASV)at an MOI of 1 (FIG. 5Q) or 10 (FIG. 5R). FIGS. 5S and 5T show theinhibitory activities of QL-XII-47 and QL-XII-56 against Venezuelanequine encephalitis virus (VEEV) at an MOI of 0.5 (FIG. 5S) or 1 (FIG.5T). FIGS. 5U and 5V show the inhibitory activities of QL-XII-47 andQL-XII-56 against Rift Valley fever virus (RVFV) at an MOI of 1 (FIG.5U) or 5 (FIG. 5V).

FIGS. 6A and 6B show that Bmx is not the target mediating QL-XII-47'santi-DENV activity. RNAi-mediated depletion of Bmx kinase with a MISSIONsiRNA pool (Sigma) has no effect on DENV yield (FIG. 6A). PCI-32765 alsohas no effect on DENV yield (FIG. 6B). Compounds were added 1 hourpost-infection with DENV2 NGC at an MOI of 1. Viral yield was quantifiedby FFA at 24 h post-infection.

FIG. 7 depicts a crystal structure of QL-X-138 with T790M EGFR. Acovalent bond formed between QL-X-138 and Cys797 is indicated.

FIGS. 8A and 8B illustrate the identification of candidate targets by“click-chemistry.” FIG. 8A shows that QL-XII-47AL retains potentanti-DENV activity. Huh7 cells were infected with DENV2 NGC at an MOI of1; compounds were added at a final concentration of 3 μM at 1 hpost-infection. Viral yields were quantified by FFA at 24 hpost-infection. FIG. 8B illustrates the treatment of DENV-infected cellswith QL-XII-47AL followed by labeling of covalently modified targetswith biotinylated azide, capture, and identification by massspectrometry.

FIGS. 9A and 9B show the result of modeling the inventive compounds withALH1. FIG. 9A shows the chemical structures of the compounds used in themodeling. FIG. 9B depicts a molecular modeling of QL-XII-47 with ALDH1.The result shows that the acrylamide moiety of QL-XII-47 is positionedtowards Cys302.

FIGS. 10A to 10C show that QL-XII-47 inhibited DENV2 viral production.Huh7 cells were infected with DENV virus. Values of FFU (focus formingunits)/ml were decreased for the infected cells treated with QL-XII-47after about 12 hours of infection compared to the infected cells nottreated with a compound of the invention (FIG. 10A). Viral count wasalso decreased for the infected cells treated with QL-XII-47 after about12 hours of infection compared to the infected cells not treated with acompound of the invention (FIG. 10B). FIG. 10C shows Western blotanalysis of DENV proteins NS3 and core, demonstrating reducedsteady-state expression of both viral proteins in the presence ofQL-XII-47 and suggesting that QL-XII-47 may prevent their expressionand/or promote their degradation.

FIG. 11 shows a schematic of the replicon experiment used to examine theeffects of QL-XII-47 on translation of the dengue RNA. PlasmidpDV2-Fluc(WT) or pDV2-FlucGDV encode dengue virus serotype 2 RNAs inwhich a luciferase reporter gene replaces most of the genes encodingcore, prM, and E. In vitro transcripts of the wildtype replicon (WT) anda mutant that cannot replicate RNA due to mutations in the active siteof the viral polymerase (GDV mutant) were produced. Huh7 cells wereelectroporated with the respective DV2-replicon RNAs. Directly afterelectroporation cells are incubated with the indicated drug (QL-XII-47 2μM, cycloheximide 30 μg/ml, MPA 5 μM). At the indicated timepost-electroporation, luminescence was measured as a marker oftranslation. For the WT construct, luc activity at an early time point(12 hours or less) reflect translation of the input RNA delivered byelectroporation; luc activity at later time points reflects luctranslated from both input and newly synthesized replicon RNA. Since theGDV mutant cannot synthesize new viral RNA, luciferase activity observedat all time points is the product of the input RNA delivered byelectroporation.

FIGS. 12A and 12B show luciferase measurements taken in the experimentdescribed in FIG. 11. FIG. 12A shows the luciferase activity measured at6 hours post-electroporation for Huh7 cells electroporated with thewildtype (WT) or mutant (MUT) replicon RNAs and then treated with 2 μMQL-XII-47, 2 μM QL-XII-56, 30 μg/mL cycloheximide (CHX) as generalinhibitor of translation, or DMSO as a negative control. FIG. 12B showsluciferase activity measured at the indicated time point for cellselectroporated with the WT or GVD replicon RNA and then treated withDMSO, QL-XII-47, QL-XII-56, or cycloheximide as indicated.

FIGS. 13A to 13C show that QL-XII-47 inhibited EMCV-IRES dependanttranslation in Huh7 cells. Huh7 cells were electroporated with an invitro transcribed RNA encoding luciferase under the control of the EMCVIRES. Following electroporation, cell were treated with QL-XII-47 2 μM,cycloheximide 30 μg/ml, MPA 5 μM as indicated on the plot. Cells werelysed and luciferase activity measured at the indicated time pointspost-electroporation. FIG. 13A shows the WT results. FIG. 13B shows theGDV results. FIG. 13C shows the EMC-Luc results.

FIG. 14 shows cytotoxicity evaluation of the exemplary compounds.

FIGS. 15A and 15B show that QL-XII-47 and QL-XII-56 inhibitedencephalomyocarditis virus (EMCV) IRES-dependant translation. FIG. 15Ashows the Cap-dependent results. FIG. 15B shows the IRES-dependentresults.

FIG. 16 shows that conjugation of QL-XII-47 to biotin significantlyreduces the antiviral activity.

FIGS. 17A and 17B show the effects of RNAi-mediated depletion of Prdx-1on dengue virus. Cells were treated with individual (sil-si4) and pooledsiRNAs against Prdx-1 for 48 hours and then infected with DV2 at moi 1.Cells were lysed, and culture supernatants were harvested at 24 hourspost-infection. FIG. 17A shows that RNAi-mediated depletion of Prdx-1does not reduce steady-state expression of dengue NS3 protein (left);moreover, combination treatment of cells with siRNAs against Prdx-1 andQL-XII-47 does not reduce steady-state expression of NS3 beyond what isobserved with QL-XII-47 alone. FIG. 17B shows the quantitation ofinfectious viral particles released to the culture supernatants at 24hours post-infection showing that RNAi-mediated depletion of Prdx-1 doesnot appear to inhibit dengue virus.

FIGS. 18A and 18B show that QL-XII-47 and QL-XII-56 inhibited vesicularstomatitis virus (VSV). FIG. 18A shows the VSV 6 hpi results. FIG. 18Bshows the RTqPCR results.

FIGS. 19A and 19B show that QL-XII-47 and QL-XII-56 inhibited poliovirusType 1 (PV1). FIG. 19A shows the PV1 6 hpi results. FIG. 19B shows theRTqPCR results.

FIGS. 20A to 20H show the exemplary compounds prepared according toformulae (I)-(III) and (a)-(c). The blue bonds in the structures of thesecond column and the red bonds in the structures of the third columnindicate the point of attachment to the scaffold formulae.

FIGS. 21A and 21B show recombinant viral particle or reporter viralparticle (RVP) screening of the exemplary compounds. FIG. 21A shows theresults when the concentration of each compound was 5.3 μM or 1.9 μM.FIG. 21B shows the results when the concentration of each compound was2.5 μM. Used in the system are the particles with dengue structuralproteins (E, prM/M, and core) and then an RNA derived from West Nilevirus that encodes the nonstructural proteins as well as a luciferasereporter (Ansarah-Sobrinho et al., Virology, 2008, 381, 67-74). Theresulting particle can infect new cells. Upon viral entry and releaseand translation of the WNV RNA, luc expression is obtained. The lucactivity is a marker of steady-state viral RNA. Decreased luc activitycan reflect inhibition of the initial entry step OR inhibition oftranslation of the viral RNA OR inhibition of steady-state RNAreplication (increased synthesis and/or decreased turnover).

FIG. 22 shows FFA evaluation of the exemplary compounds.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention provides compounds, and pharmaceuticalcompositions thereof, for the prevention and treatment of infectiousdiseases in a subject. The infectious disease may be caused by a virus,for example, Flaviviridae virus (e.g., Dengue virus (DENV), includingDengue virus 1 (DENV1), Dengue virus 2 (DENV2), Dengue virus 3 (DENV3),and Dengue virus 4 (DENV4); West Nile virus; tick-borne encephalitisvirus; yellow fever virus; hepatitis C virus; hepatitis G virus; bovineviral diarrhea; classical swine fever virus; and hog cholera virus),Kunjin virus, Japanese encephalitis virus, vesicular stomatitis virus(VSV), vesicular stomatitis virus (VSV) pseudotyped with rabiesglycoprotein, vesicular stomatitis virus (VSV) pseudotyped with Ebolaglycoprotein, herpes simplex virus 1 (HSV-1), human cytomegalovirus(HCMV), poliovirus, Junin virus, Ebola virus, Marburg virus (MARV),Lassa fever virus (LASV), Venezuelan equine encephalitis virus (VEEV),Rift Valley Fever virus (RVFV), hepatitis B virus, cytomegalovirus,papillomavirus, coronavirus, Epstein-Barr virus (EBV), humanimmunodeficiency virus (HIV), orthomyxovirus, paramyxovirus, arenavirus,bunyavirus, adenovirus, poxvirus, retrovirus, rhabdovirus, picornavirus,or herpesvirus. In certain embodiments, the compound inhibits theactivity of the virus. In certain embodiments, the compound inhibits theactivity of the virus by covalently modifying one or more cysteineresidues of a host factor. In certain embodiments, the compound preventsor inhibits entry of the virus into a host cell. The present inventionfurther provides methods of using the compounds described herein, e.g.,as biological probes to study the inhibition of the activity of a virus,to study viral entry, and to screen a library of compounds to identifyantiviral compounds, and as therapeutics, e.g., in the prevention andtreatment of infectious diseases caused by a virus. The infectiousdiseases include, but are not limited to, Dengue fever, Denguehemorrhagic fever (DHF), Dengue shock syndrome (DSS), hepatitis B,hepatitis C, fulminant viral hepatitis, severe acute respiratorysyndrome (SARS), viral myocarditis, influenza A virus infection,influenza B virus infection, parainfluenza virus infection, RS virus(RSV) infections (e.g., RSV bronchiolitis, RSV pneumonia, especiallyinfant and childhood RSV infections and RSV pneumonia in the patientswith cardiopulmonary disorders), measles virus infection, vesicularstomatitis virus infection, rabies virus infection, Ebola virusinfection, Japanese encephalitis, Junin virus infection, humancytomegalovirus infection, herpes simplex virus 1 infection, poliovirusinfection, Marburg virus infection, Lassa fever virus infection,Venezuelan equine encephalitis, Rift Valley Fever virus infection,Korean hemorrhagic fever virus infection, Crimean-Congo hemorrhagicfever virus infection, HIV infection, encephalitis, Saint Louiseencephalitis, Kyasanur Forest disease, Murray Valley encephalitis,tick-borne encephalitis, West Nile encephalitis, yellow fever, and viralinfections in subjects with immune disorders. Novel compounds have beenidentified and optimized that target essential host factors to furtherthe understanding of host-virus interactions and to validate hosttargets and lead compounds for further development as a potential newclass of antiviral agents. Importantly, because the novel compounds actvia a host target, they have the potential to have activity againstmultiple pathogens that utilize the same host factor or pathway and tocircumvent the rapid selection for resistance observed with agents thatact via a viral target.

Successful antiviral drug development efforts have traditionally focusedon inhibition of viral enzymes that are responsible for catalyzing viralgenome replication and polyprotein processing during viral assembly.Lessons from HIV drug development efforts teach that, due to the highmutation rates of RNA viruses and the associated rapid development ofresistance to monotherapies, combination therapies targeting multiplestages of the viral life cycle are necessary for effective treatmentwithout the rapid development of resistance. As demonstrated by CCR5antagonists such as the anti-HIV drug maraviroc, host-targetedantivirals can also contribute to combination antiviral therapies and,in some cases, may prove superior over the long term because thehost-targeted antivirals have the potential to be effective againstmultiple viral pathogens and because their barriers to resistance arehigher than those of drugs that act via viral targets.

A large number of cellular proteins have a reactive cysteine that isimportant as a catalytic residue or as a site of post-translationalmodification and that can be selectively targeted by a compound thatbinds and places a reactive group in close proximity to the targetedcysteine. Chemical proteomic studies have identified a large number ofproteins that contain reactive cysteines (the reactive “cysteinome”) andhave established that reactivity in most cases corresponds to residuesof significant biological function (Weerapana et al., Nature Chem. Biol.(2008) 4:405-407; and Weerapana et al., Nature (2010) 468:790-795). Thestrategy of the present invention is to target essential host factors bydeveloping selective, covalent cysteine-directed inhibitors. Covalentinhibition has several potential benefits, including (1) irreversibleinactivation of the target protein that mitigates the need toextensively optimize for potency; (2) full modification of the targetwith transient exposure of the drug in vivo, which can reduce the needto achieve high and sustained drug exposure and therefore mitigatetoxicology concerns; and (3) facilitation of target identification byaffinity approaches. The success of covalent inhibitors iswell-illustrated by the thirty-nine FDA-approved drugs that are highlyeffective in humans, including aspirin (Warner et al., Proc. Nat. Acad.Sci. USA (2002) 99:13371-13373) (Cox-1, Cox-2, and Cox-3) and the largepenicillin-class of antibiotics (bacterial DD-transpeptidase inhibitors)(Waxman et al., Ann. Rev. Biochem. (1983) 52:825-869), amongst manyothers (Johnson et al., Future Med. Chem. (2010) 2:949-964; and Singh etal., Nat. Rev. Drug Discov. (2011) 10:307-317).

Small molecule inhibitors have been developed that form a covalent bondto a free cysteine of a target protein. While this strategy has beenapplied to the development of covalent kinase inhibitors, a significantopportunity exists to apply this approach to discover novel antiviraltargets as well as to develop and validate potent antiviral compoundsthat act via these targets. This approach complements on-going effortsto develop non-covalent inhibitors targeting essential viral proteins.

Although structure-guided drug discovery approaches have traditionallybeen biased against covalent inhibitors due to concerns about off-targeteffects and potential toxicity, this belies the historical success ofdrugs that act via covalent mechanisms, including thirty-nineFDA-approved drugs (Johnson et al., Future Med. Chem. (2010) 2:949-964;and Singh et al., Nat. Rev. Drug Discov. (2011) 10:307-317). Theseinclude compounds targeting enzyme and non-enzyme targets such as,rasagiline (Hubalek et al., J. Med. Chem. (2004) 47:1760-1766)(monoamine oxidase), clopidogrel (Herbert et al., Seminars in VascularMedicine (2003) 3:113-122) (G protein coupled receptor), omeprazole (Imet al., J. Biol. Chem. (1985) 260:4591-4597) (proton pump inhibitor),amongst many others (Johnson et al., Future Med. Chem. (2010) 2:949-964;and Singh et al., Nat. Rev. Drug Discov. (2011) 10:307-317).Importantly, covalent inhibitors are not simply highly reactiveelectrophiles. Specific covalent inhibitors typically have warheads thatare only weakly reactive compared to the quinones and acyl halidestypically present in highly reactive compounds and electrophilicmetabolites. In addition, covalent inhibitors usually must formspecific, non-covalent interactions and bind in a particular orientationin order to undergo covalent reaction with a nucleophile whereas highlyreactive compounds more commonly react non-specifically with thenucleophiles that are most accessible to solution on the proteinsurface.

Covalent inhibitors, when properly deployed, have several potentialadvantages over non-covalent inhibitors. First, the covalent attachmentmeans that the inhibitor has a kinetic off-rate of essentially zero.This can boost potency by several orders of magnitude. For example,WZ4002 (see FIG. 1 for the chemical structure) inhibits T790MEGFR-dependent cellular proliferation with an EC₅₀ of 10 nM, while thecorresponding non-covalent inhibitor has an EC₅₀ higher than 10 μM (Zhouet al., Nature (2009) 462:1070-1074). Second, transient exposure isoften sufficient to achieve complete modification of the target. Third,if designed and screened appropriately, very potent target modulationcan be achieved with covalent inhibitors. For example, WZ4002 wasidentified from an acrylamide-containing library and found to beefficacious in T790M EGFR-dependent lung tumor models (Zhou et al.,Nature (2009) 462:1070-1074). Fourth, since the potency of theinhibitors of the present invention relies upon their covalentmodification of a cysteine residue, the pharmacological selectivity ofthe inhibitors can be established by introducing a cysteine to serinemutation into the target enzyme and looking for reversal of theinhibitor-induced pharmacology. This approach has been used previouslyto prove that the functional target of WZ4002 is T790M EGFR and that thefunctional target of FIIN1 is FGFR (Zhou et al., Nature (2009)462:1070-1074; and Zhou et al., Chem. Biol. (2010) 17:285-295). Fifth,covalent attachment of the inhibitor can facilitate identification ofthe inhibitor's target by affinity purification. Identification of thetarget(s) of non-covalent inhibitors following phenotypic, cell-basedscreens can be more challenging in comparison. It is noted that while acysteine-directed inhibitor of the HCV protease has recently beendisclosed (Hagel et al., Nature Chem. Biol. (2011) 7:22-24).

Cysteines are functionally important as catalytic residues as well assites for numerous types of post-translational modification includingdisulfide formation, oxidation, nitrosolyation, and alkylation. Althoughthiol groups are predominantly protonated at physiological pH ranges,the pK_(a) of the thiol groups is greatly affected by the surroundingamino acids. Consequently, a thiolate can act as an extremely potentnucleophile even at physiological pH and can serve as a key catalyticresidue in several large enzyme families, including cysteine proteases,phosphatases, acyl transferases, and E2 ubiquitin transferases. Smallmolecules that are capable of covalently modifying the thiol group ofcysteine are quite frequently found in nature, and the nucleophilicityof active-site cysteines has been exploited to develop potent,irreversible inhibitors that covalently modify catalytic cysteines ofproteases, phosphatases, and E2 ubiquitin transferases (Singh et al.,Nat. Rev. Drug Discov. (2011) 10:307-317). In addition, cysteineresidues located in or near small molecule binding clefts outside of theactive site have been successfully targeted with small moleculeinhibitors.

Cysteine-targeted covalent inhibitors take advantage of non-covalentinteractions to selectively target a particular protein binding site andto position the electrophilic moiety in a conformation that permits bondformation with a specific cysteine residue. This strategy preventsnon-selective reaction of an electrophile with the cysteine-containingproteome (the “cysteineome”) and has successfully yielded inhibitorswith a remarkable level of functional selectivity in cellular assays andin vivo. For example, several inhibitors that function by this mechanismare in clinical trials, including four different compounds targeting aunique cysteine located in the periphery of the ATP-binding site of EGFRkinases. This approach has been recently applied to develop selectivecovalent inhibitors of a number of different human kinases, includinginhibitors of Rsk (CMK, FMK) (Cohen et al., Science (2005) 308:1318-1321and Cohen et al., Nature Chem. Biol. (2007) 3:156-160), BTK (PCI-32765)(Honigberg et al., Proc. Nat. Acad. Sci. USA (2010) 107:13075-13080),c-kit (Leproult et al., J. Med. Chem. (2011) 54:1347-1355), Nek2 (Heniseet al., J. Med. Chem. (2011) 54:4133-4146), and a subset of the MAPKs(resorcylic acid lactone polyketides (Schirmer et al., Proc. Nat. Acad.Sci. USA (2006) 103:4234-4239)). Studies suggest that this strategymight be applied more broadly to identify selective, irreversibleinhibitors of not only additional kinases, but other protein classes aswell. In a recent quantitative chemoproteomic study, Cravatt andcolleagues utilized an alkynylated iodoacetamide probe and quantitativemass spectrometry to identify the reactive cysteinome (Weerapana et al.,Nature (2010) 468:790-795). Out of a total of 8,910 cysteines present onthe 890 human proteins detected in this analysis, 1,082 cysteines werefound to be hyper-reactive. Importantly, hyper-reactivity was found tobe a good predictor of a cysteine's function as a catalytic residue, asa non-catalytic residue present in an enzyme active site, or as a siteof post-translational oxidative modification.

Compounds

In one aspect of the present invention, provided are compounds ofFormula (I):

or a pharmaceutically acceptable salt thereof;wherein:

Ring A is aryl, arylalkenyl, or heteroaryl;

each instance of R^(A) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═NR^(A1))R^(A1),—C(═NR^(A1))OR^(A1), —C(═NR^(A1))SR^(A1), —C(═NR^(A1))N(R^(A1))₂,—C(═O)NR^(A1), —NR^(A1)C(═O)—, —C(═O)R^(A1), —C(═S)R^(A1),—C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A1))₂, —NO₂, —N₃, —N(R^(A1))₃⁺F⁻, —N(R^(A1))₃ ⁺Cl⁻, —N(R^(A1))₃ ⁺Br⁻, —N(R^(A1))₃ ⁺I⁻,—N(OR^(A1))R^(A1), —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1),—NR^(A1)C(═O)SR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)C(═S)R^(A1),—NR^(A1)C(═S)OR^(A1), —NR^(A1)C(═S)SR^(A1), —NR^(A1)C(═S)N(R^(A1))₂,—NR^(A1)C(═NR^(A1))R^(A1), —NR^(A1)C(═NR^(A1))OR^(A1),—NR^(A1)C(═NR^(A1))SR^(A1), —NR^(A1)C(═NR^(A1))N(R^(A1))₂,—NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)₂OR^(A1), —NR^(A1)S(═O)₂SR^(A1),—NR^(A1)S(═O)₂N(R^(A1))₂, —NR^(A1)S(═O)R^(A1), —NR^(A1)S(═O)OR^(A1),—NR^(A1)S(═O)SR^(A1), —NR^(A1) S(═O)N(R^(A1))₂, —NR^(A1)P(═O),—NR^(A1)P(═O)₂, —NR^(A1)P(═O)(R^(A1))₂, —NR^(A1)P(═)R^(A1)(OR^(A1)),—NR^(A1)P(═O)(OR^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —OC(═NR^(A1))R^(A1), —OC(═NR^(A1))OR^(A1),—OC(═NR^(A1))N(R^(A1))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A1))₂, —ON(R^(A1))₂, —OS(═O)R^(A1), —OS(═O)OR^(A1),—OS(═O)SR^(A1), —OS(═O)N(R^(A1))₂, —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),—OS(═O)₂SR^(A1), —OS(═O)₂N(R^(A1))₂, —OP(═O)₂, —OP(═O)(R^(A1))₂,—OP(═O)R^(A1)(OR^(A1)), —OP(═O)(OR^(A1))₂, —OP(═O), —OP(R^(A1))₂,—OPR^(A1)(OR^(A1)), —OP(OR^(A1))₂, —OSi(R^(A1))₃, —OSi(R^(A1))₂OR^(A1),—OSi(R^(A1))(OR^(A1))₂, —OSi(OR^(A1))₃, —SSR^(A1), —S(═O)R^(A1),—S(═O)OR^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1),—S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A1))₂, —P(R^(A1))₂, —PR^(A)(OR^(A1)), —P(OR^(A1))₂, —P(═O),—P(═O)(R^(A1))₂, —P(═O)(OR^(A1))₂, —P(═O)R^(A1)(OR^(A1)), —P(═O)₂,—B(R^(A1))₂, —B(OR^(A1))₂, —BR^(A1)(OR^(A1)), —Si(R^(A1))₃,—Si(R^(A1))₂R^(A1), —SiR^(A1)(OR^(A1))₂, and —Si(OR^(A1))₃, wherein eachoccurrence of R^(A1) is independently selected from the group consistingof hydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, anitrogen protecting group when attached to a nitrogen atom, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, or two R^(A1) groups are joined toform an optionally substituted heterocyclic ring;

k is 0, 1, 2, 3, 4, or 5;

Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring;

each instance of R^(C) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(C1), —N(R^(C1))₂, —SR^(C1), —CN, —C(═NR^(C1))R^(C1),—C(═NR^(C1))OR^(C1), —C(═NR^(C1))SR^(C1), —C(═NR^(C1))N(R^(C1))₂,—C(═O)R^(C1), —C(═S)R^(C1), —C(═S)OR^(C1), —C(═S)SR^(C1),—C(═S)N(R^(C1))₂, —NO₂, —N₃, —N(R^(C1))₃ ⁺F⁻, —N(R^(C1))₃ ⁺Cl⁻,—N(R^(C1))₃ ⁺Br⁻, —N(R^(C1))₃+, —N(OR^(C1))R^(C1), —NR^(C1)C(═O)R^(C1),—NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1), —NR^(C1)C(═O)N(R^(C1))₂,—NR^(C1)C(═S)R^(C1), —NR^(C1)C(═S)OR^(C1), —NR^(C1)C(═S)SR^(C1),—NR^(C1)C(═S)N(R^(C1))₂, —NR^(C1)C(═NR^(C1))R^(C1),—NR^(C1)C(═NR^(C1))OR^(C1), —NR^(C1)C(═NR^(C1))SR^(C1),—NR^(C1)C(═NR^(C1))N(R^(C1))₂, —NR^(C1)S(═O)₂R^(C1),—NR^(C1)S(═O)₂OR^(C1), —NR^(C1)S(═O)₂SR^(C1), —NR^(C1)S(═O)₂N(R^(C1))₂,—NR^(C1)S(═O)R^(C1), —NR^(C)S(═O)OR^(C1), —NR^(C)S(═O)SR^(C1),—NR^(C1)S(═O)N(R^(C1))₂, —NR^(C1)P(═O), —NR^(C1)P(═O)₂,—NR^(C1)P(═O)(R^(C1))₂, —NR^(C1)P(═O)R^(C1)(OR),—NR^(C1)P(═O)(OR^(C1))₂, —OC(═O)R^(C1), —OC(═O)OR^(C1), —OC(═O)SR^(C1),—OC(═O)N(R^(C1))₂, —OC(═NR^(C1))R^(C1), —OC(═NR^(C1))OR^(C1),—OC(═NR^(C1))N(R^(C1))₂, —OC(═S)R^(C1), —OC(═S)OR^(C1), —OC(═S)SR^(C1),—OC(═S)N(R^(C1))₂, —ON(R^(C1))₂, —OS(═O)R^(C1), —OS(═O)OR^(C1),—OS(═O)SR^(C1), —OS(═O)N(R^(C1))₂, —OS(═O)₂R^(C1), —OS(═O)₂OR^(C1),—OS(═O)₂SR^(C1), —OS(═O)₂N(R^(C1))₂, —OP(═O)₂, —OP(═O)(R^(C1))₂,—OP(═O)R1(OR^(C1)), —OP(═O)(OR^(C1))₂, —OP(═O), —OP(R^(C1))₂,—OPR^(C1)(OR^(C1)), —OP(OR^(C1))², —OSi(R^(C1))₃, —OSi(R^(C1))₂OR^(C1),—OSi(R^(C1))(OR^(C1))₂, —OSi(OR^(C1))₃, —SSR^(C1), —S(═O)R^(C1),—S(═O)OR^(C1), —S(═O)N(R^(C1))₂, —S(═O)₂R^(C1), —S(═O)₂R^(C1),—S(═O)₂R^(C1), —S(═O)₂N(R^(C1))₂, —SC(═O)R^(C1), —SC(═O)OR^(C1),—SC(═O)SR^(C1), —SC(═O)N(R^(C1))₂, —SC(═S)R^(C1), —SC(═S)OR^(C1),—SC(═S)SR^(C1), —SC(═S)N(R^(C1))₂, —P(R^(C1))₂, —PR^(C1)(OR^(C1)),—P(OR^(C1))₂, —P(═O), —P(═O)(R^(C1))₂, —P(═O)(OR^(C1))₂,—P(═O)R^(C1)(OR^(C1)), —P(═O)₂, —B(R^(C1))₂, —B(OR^(C1))₂,—BR^(C1)(OR^(C1)), —Si(R^(C1))₃, —Si(R^(C1))₂OR^(C1),—SiR^(C1)(OR^(C1))₂, and —Si(OR^(C1))₃, wherein each occurrence ofR^(C1) is independently selected from the group consisting of hydrogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, a nitrogenprotecting group when attached to a nitrogen atom, an oxygen protectinggroup when attached to an oxygen atom, a sulfur protecting group whenattached to a sulfur atom, or two R^(C1) groups are joined to form anoptionally substituted heterocyclic ring or optionally substitutedheteroaryl ring;

n is 0, 1, 2, 3, or 4;

L is a bond or an optionally substituted, branched or unbranched C₁₋₆hydrocarbon chain;

R^(D) is any one of Formulae (i-1)-(i-43):

wherein:

each instance of R^(D1) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a),—CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a),—C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a),—C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a),—C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1a), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

each instance of R^(D2) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a),—CH₂N(R^(D2a))₂, —CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a),—C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a),—C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a),—C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and—C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, or two R^(D2a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

each instance of R^(D3) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a),—CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a),—C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a),—C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring;

R^(D4) is a leaving group selected from the group consisting of —Br,—Cl, —I, and —OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

each instance of X¹ is independently a bond, —C(═O)—, —SO₂—, —NR^(D5)—,optionally substituted alkylene, or optionally substitutedheteroarylene, wherein R^(D5) is hydrogen, C₁₋₆ alkyl, or a nitrogenprotecting group;

each instance of Y is independently O, S, or NR^(D6), wherein R^(D6) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; and

each instance of z and z₁ is independently 0, 1, 2, 3, 4, 5, or 6, asvalency permits.

In another aspect of the present invention, provided are compounds ofFormula (II):

or a pharmaceutically acceptable salt thereof;wherein:

Ring A is aryl, arylalkenyl, or heteroaryl;

each instance of R^(A) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═NR^(A1))R^(A1),—C(═NR^(A1))OR^(A1), —C(═NR^(A1))SR^(A1), —C(═NR^(A1))N(R^(A1))₂,—C(═O)NR^(A1)—, —NR^(A1)C(═O)—, —C(═O)R^(A1), —C(═S)R^(A1),—C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A1))₂, —NO₂, —N₃, —N(R^(A1))₃⁺F⁻, —N(R^(A1))₃ ⁺Cl⁻, —N(R^(A1))₃ ⁺Br⁻, —N(R^(A1))₃ ⁺I⁻,—N(OR^(A1))R^(A1), —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1),—NR^(A1)C(═O)SR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)C(═S)R^(A1),—NR^(A1)C(═S)OR^(A1), —NR^(A1)C(═S)SR^(A1), —NR^(A1)C(═S)N(R^(A1))₂,—NR^(A1)C(═NR^(A1))R^(A1), —NR^(A1)C(═NR^(A1))OR^(A1),—NR^(A1)C(═NR^(A1))SR^(A1), —NR^(A1)C(═NR^(A1))N(R^(A1))₂,—NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)₂OR^(A1), —NR^(A1)S(═O)₂SR^(A1),—NR^(A1)S(═O)₂N(R^(A1))₂, —NR^(A1)S(═O)R^(A1), —NR^(A1)S(═O)OR^(A1),—NR^(A1)S(═O)SR^(A1), —NR^(A1)S(═O)N(R^(A1))₂, —NR^(A1)P(═O),—NR^(A1)P(═O)₂, —NR^(A1)P(═O)(R^(A1))₂, —NR^(A1)P(═)R^(A1)(OR^(A1)),—NR^(A1)P(═O)(OR^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —OC(═NR^(A1))R^(A1), —OC(═NR^(A1))OR^(A1),—OC(═NR^(A1))N(R^(A1))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A1))₂, —ON(R^(A1))₂, —OS(═O)R^(A1), —OS(═O)OR^(A1),—OS(═O)SR^(A1), —OS(═O)N(R^(A1))₂, —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),—OS(═O)₂SR^(A1), —OS(═O)₂N(R^(A1))₂, —OP(═O)₂, —OP(═O)(R^(A1))₂,—OP(═O)R^(A1)(OR^(A1)), —OP(═O)(OR^(A1))₂, —OP(═O), —OP(R^(A1))₂,—OPR^(A1)(OR^(A1)), —OP(OR^(A1))₂, —OSi(R^(A1))₃, —OSi(R^(A1))₂OR^(A1),—OSi(R^(A1))(OR^(A1))₂, —OSi(OR^(A1))₃, —SSR^(A1), —S(═O)R^(A1),—S(═O)OR^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1),—S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A1))₂, —P(R^(A1))₂, —PR^(A)(OR^(A1)), —P(OR^(A1))₂, —P(═O),—P(═O)(R^(A1))₂, —P(═O)(OR^(A1))₂, —P(═O)R^(A1)(OR^(A1)), —P(═O)₂,—B(R^(A1))₂, —B(OR^(A1))₂, —BR^(A1)(OR^(A1)), —Si(R^(A1))₃,—Si(R^(A1))₂R^(A1), —SiR^(A1)(OR^(A1))₂, and —Si(OR^(A1))₃, wherein eachoccurrence of R^(A1) is independently selected from the group consistingof hydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, anitrogen protecting group when attached to a nitrogen atom, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, or two R^(A1) groups are joined toform an optionally substituted heterocyclic ring;

k is 0, 1, 2, 3, 4, or 5;

Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring;

each instance of R^(j1), R^(j2), R^(j3), and R^(C) is independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(C1), —N(R^(C1))₂, —SR^(C1), —CN,—C(═NR^(C1))R^(C1), —C(═NR^(C1))OR^(C1), —C(═NR^(C1))SR^(C1),—C(═NR^(C1))N(R^(C1))₂, —C(═O)R^(C1), —C(═S)R^(C1), —C(═S)OR^(C1),—C(═S)SR^(C1), —C(═S)N(R^(C1))₂, —NO₂, —N₃, —N(R^(C1))₃ ⁺F⁻, —N(R^(C1))₃⁺Cl⁻, —N(R^(C1))₃ ⁺Br⁻, —N(R^(C1))₃ ⁺I⁻, —N(OR^(C1))R^(C1),—NR^(C1)C(═O)R^(C1), —NR^(C1)C_((═O))OR^(C1), —NR^(C)C(═O)SR^(C1),—NR^(C1)C(═O)N(R^(C1))₂, —NR^(C1)C(═S)R^(C1), —NR^(C1)C(═S)OR^(C1),—NR^(C1)C(═S)SR^(C1), —NR^(C1)C(═S)N(R^(C1))₂,—NR^(C1)C(═NR^(C1))R^(C1), —NR^(C1)C(═NR^(C1))OR^(C1),—NR^(C1)C(═NR^(C1))SR^(C1) NR^(C1)C(═NR^(C1))N(R^(C1))₂,—NR^(C1)S(═O)₂R^(C1), —NR^(C1)S(═O)₂OR^(C1), —NR^(C1)S(═O)₂SR^(C1),—NR^(C1)S(═O)₂N(R^(C1))₂, —NR^(C1)S(═O)R^(C1), —NR^(C)S(═O)OR^(C1),—NR^(C)S(═O)SR^(C1), —NR^(C1)S(═O)N(R^(C1))₂, —NR^(C) P(═O), —NR^(C)P(═O)₂, —NR^(C1)P(═O)(R^(C1))₂, —NR^(C1)P(═O)R(OR^(C1)),—NR^(C1)P(═O)(OR^(C1))₂, —OC(═O)R^(C1), —OC(═O)OR^(C1), —OC(═O)SR^(C1),—OC(═O)N(R^(C1))₂, —OC(═NR^(C1))R^(C1), —OC(═NR^(C1))OR^(C1),—OC(═NR^(C1))N(R^(C1))₂, —OC(═S)R^(C1), —OC(═S)OR^(C1), —OC(═S)SR^(C1),—OC(═S)N(R^(C1))₂, —ON(R^(C1))₂, —OS(═O)R^(C1), —OS(═O)OR^(C1),—OS(═O)SR^(C1), —OS(═O)N(R^(C1))₂, —OS(═O)₂R^(C1), —OS(═O)₂OR^(C1),—OS(═O)₂SR^(C1), —OS(═O)₂N(R^(C1))₂, —OP(═O)₂, —OP(═O)(R^(C1))₂,—OP(═O)R^(C1)(OR^(C1)), —OP(═O)(OR^(C1))₂, —OP(═O), —OP(R^(C1))₂,—OPR^(C1)(OR^(C1)), —OP(OR^(C1))₂, —OSi(R^(C1))₃, —OSi(R^(C1))₂OR^(C1),—OSi(R^(C1))(OR^(C1))², —OSi(OR^(C1))₃, —SSR^(C1), —S(═O)R^(C1),—S(═O)OR^(C1), —S(═O)N(R^(C1))₂, —S(═O)₂R^(C1), —S(═O)₂R^(C1),—S(═O)₂R^(C1), —S(═O)₂N(R^(C1))₂, —SC(═O)R^(C1), —SC(═O)OR^(C1),—SC(═O)SR^(C1), —SC(═O)N(R^(C1))₂, —SC(═S)R^(C1), —SC(═S)OR^(C1),—SC(═S)SR^(C1), —SC(═S)N(R^(C1))₂, —P(R^(C1))₂, —PR^(C1)(OR^(C1)),—P(OR^(C1))₂, —P(═O), —P(═O)(R^(C1))₂, —P(═O)(OR^(C1))₂,—P(═O)R^(C1)(OR^(C1)), —P(═O)₂, —B(R^(C1))₂, —B(OR^(C1))₂,—BR^(C1)(OR^(C1)), —Si(R^(C1))₃, —Si(R^(C1))₂OR^(C1),—SiR^(C1)(OR^(C1))₂, and —Si(OR^(C1))₃, wherein each occurrence ofR^(C1) is independently selected from the group consisting of hydrogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, a nitrogenprotecting group when attached to a nitrogen atom, an oxygen protectinggroup when attached to an oxygen atom, a sulfur protecting group whenattached to a sulfur atom, or two R^(C1) groups are joined to form anoptionally substituted heterocyclic ring or optionally substitutedheteroaryl ring;

n is 0, 1, 2, 3, or 4;

L is a bond or an optionally substituted, branched or unbranched C₁₋₆hydrocarbon chain;

R^(D) is any one of Formulae (i-1)-(i-43):

wherein:

each instance of R^(D1) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a),—CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a),—C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a),—C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a),—C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

each instance of R^(D2) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a),—CH₂N(R^(D2a))₂, —CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a),—C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a),—C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a),—C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and—C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, or two R^(D2a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

each instance of R^(D3) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a),—CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a),—C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a),—C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring;

R^(D4) is a leaving group selected from the group consisting of —Br,—Cl, —I, and —OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

each instance of X¹ is independently a bond, —C(═O)—, —SO₂—, —NR^(D5)—,optionally substituted alkylene, or optionally substitutedheteroarylene, wherein R^(D5) is hydrogen, C14 alkyl, or a nitrogenprotecting group;

each instance of Y is independently O, S, or NR^(D6), wherein R^(D6) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; and

each instance of z and z₁ is independently 0, 1, 2, 3, 4, 5, or 6, asvalency permits.

In another aspect of the present invention, provided are compounds ofFormula (III):

or a pharmaceutically acceptable salt thereof;wherein:

Ring A is aryl, arylalkenyl, or heteroaryl;

each instance of R^(A) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═NR^(A1))R^(A1),—C(═NR^(A1))OR^(A1), —C(═NR^(A1))SR^(A1), —C(═NR^(A1))N(R^(A1))₂,—C(═O)NR^(A1)—, —NR^(A1)C(═O)—, —C(═O)R^(A1), —C(═S)R^(A1),—C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A1))₂, —NO₂, —N₃, —N(R^(A1))₃⁺F⁻, —N(R^(A1))₃ ⁺Cl⁻, —N(R^(A1))₃ ⁺Br⁻, —N(R^(A1))₃ ⁺I⁻,—N(OR^(A1))R^(A1), —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1),—NR^(A1)C(═O)SR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)C(═S)R^(A1),—NR^(A1)C(═S)OR^(A1), —NR^(A1)C(═S)SR^(A1), —NR^(A1)C(═S)N(R^(A1))₂,—NR^(A1)C(═NR^(A1))R^(A1), —NR^(A1)C(═NR^(A1))OR^(A1),—NR^(A1)C(═NR^(A1))SR^(A1), —NR^(A1)C(═NR^(A1))N(R^(A1))₂,—NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)₂OR^(A1), —NR^(A1)S(═O)₂SR^(A1),—NR^(A1)S(═O)₂N(R^(A1))₂, —NR^(A1)S(═O)R^(A1), —NR^(A1)S(═O)OR^(A1),—NR^(A1)S(═O)SR^(A1), —NR^(A1)S(═O)N(R^(A1))₂, —NR^(A1)P(═O),—NR^(A1)P(═O)₂, —NR^(A1)P(═O)(R^(A1))₂, —NR^(A1)P(═O)R^(A1)(OR^(A1)),—NR^(A1)P(═O)(OR^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(AC1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —OC(═NR^(A1))R^(A1), —OC(═NR^(A1))OR^(A1),—OC(═NR^(A1))N(R^(A1))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A1))₂, —ON(R^(A1))₂, —OS(═O)R^(A1), —OS(═O)OR^(A1),—OS(═O)SR^(A1), —OS(═O)N(R^(A1))₂, —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),—OS(═O)₂SR^(A1), —OS(═O)₂N(R^(A1))₂, —OP(═O)₂, —OP(═O)(R^(A1))₂,—OP(═O)R^(A1)(OR^(A1)), —OP(═O)(OR^(A1))₂, —OP(═O), —OP(R^(A1))₂,—OPR^(A1)(OR^(A1)), —OP(OR^(A1))₂, —OSi(R^(A1))₃, —OSi(R^(A1))₂OR^(A1),—OSi(R^(A1))(OR^(A1))₂, —OSi(OR^(A1))₃, —SSR^(A1), —S(═O)R^(A1),—S(═O)OR^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1),—S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A1))₂, —P(R^(A1))₂, —PR^(A1)(OR^(A1)), —P(OR^(A1))₂, —P(═O),—P(═O)(R^(A1))₂, —P(═O)(OR^(A1))₂, —P(═O)R^(A1)(OR^(A1)), —P(═O)₂,—B(R^(A1))₂, —B(OR^(A1))₂, —BRA(OR^(A1)), —Si(R^(A1))₃,—Si(R^(A1))₂OR^(A1), —SiR^(A1)(OR^(A1))₂, and —Si(OR^(A1))₃, whereineach occurrence of R^(A1) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(A1) groups are joined to form an optionally substituted heterocyclicring;

k is 0, 1, 2, 3, 4, or 5;

Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring;

each instance of R^(C) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(C1), —N(R^(C1))₂, —SR^(C1), —CN, —C(═NR^(C1))R^(C1),—C(═NR^(C1))OR^(C1), —C(═NR^(C1))SR^(C1), —C(═NR^(C1))N(R^(C1))₂,—C(═O)R^(C1), —C(═S)R^(C1), —C(═S)OR^(C1), —C(═S)SR^(C1),—C(═S)N(R^(C1)) 2, —NO₂, —N₃, —N(R^(C1))₃+F—, —N(R^(C1))₃ ⁺Cl⁻,—N(R^(C1))₃ ⁺Br⁻, —N(R^(C1))₃+, —N(OR^(C1))R^(C1), —NR^(C1)C(═O)R^(C1),—NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1), —NR^(C1)C(═O)N(R^(C1))₂,—NR^(C1)C(═S)R^(C1), —NR^(C1)C(═S)OR^(C1), —NR^(C1)C(═S)SR^(C1),—NR^(C1)C(═S)N(R^(C1))₂, —NR^(C1)C(═NR^(C1))R^(C1),—NR^(C1)C(═NR^(C1))OR^(C1), —NR^(C1)C(═NR^(C1))SR^(C1)NR^(C1)C(═NR^(C1))N(R^(C1))₂, —NR^(C1)S(═O)₂R1, —NR^(C1)S(═O)₂OR^(C1),—NR^(C1)S(═O)₂SR^(C1), —NR^(C1)S(═O)₂N(R^(C1))₂, —NR^(C1)S(═O)R^(C1),—NR^(C1)S(═O)OR^(C1), —NR^(C1)S(═O)SR^(C1), —NR^(C1)S(═O)N(R^(C1))₂,—NR^(C) P(═O), —NR^(C) P(═O)₂, —NR^(C1)P(═O)(R^(C1))₂, —NR^(C)P(═O)R^(C)(OR^(C1)), —NR^(C1)P(═O)(OR^(C1))₂, —OC(═O)R^(C1),—OC(═O)OR^(C1), —OC(═O)SR^(C1), —OC(═O)N(R^(C1))₂, —OC(═NR^(C1))R^(C1),—OC(═NR^(C1))OR^(C1), —OC(═NR^(C1))N(R^(C1))₂, —OC(═S)R^(C1),—OC(═S)OR^(C1), —OC(═S)SR^(C1), —OC(═S)N(R^(C1))₂, —ON(R^(C1))₂,—OS(═O)R^(C1), —OS(═O)OR^(C1), —OS(═O)SR^(C1), —OS(═O)N(R^(C1))₂,—OS(═O)₂R^(C1), —OS(═O)₂OR^(C1), —OS(═O)₂SR^(C1), —OS(═O)₂N(R^(C1))₂,—OP(═O)₂, —OP(═O)(R^(C1))₂, —OP(═O)R^(C1)(OR^(C1)), —OP(═O)(OR^(C1))₂,—OP(═O), —OP(R^(C1))₂, —OPR^(C1)(OR^(C1)), —OP(OR^(C1))₂, —OSi(R^(C1))₃,—OSi(R^(C1))₂OR^(C1), —OSi(R^(C1))(OR^(C1))₂, —OSi(OR^(C1))₃, —SSR^(C1),—S(═O)R^(C1), —S(═O)OR^(C1), —S(═O)N(R^(C1))₂, —S(═O)₂R^(C1),—S(═O)₂OR^(C1), —S(═O)₂, —S(═O)₂N(R^(C1))₂, —SC(═O)R^(C1),—SC(═O)OR^(C1), —SC(═O)SR^(C1), —SC(═O)N(R^(C1))₂, —SC(═S)R^(C1),—SC(═S)OR^(C1), —SC(═S)SR^(C1), —SC(═S)N(R^(C1))₂, —P(R^(C1))₂,—PR^(C1)(OR^(C1)), —P(OR^(C1))₂, —P(═O), —P(═O)(R^(C1))₂,—P(═O)(OR^(C1))₂, —P(═O)R^(C1)(OR^(C1)), —P(═O)₂, —B(R^(C1))₂,—B(OR^(C1))₂, —BR^(C1)(OR^(C1)), —Si(R^(C1))₃, —Si(R^(C1))₂OR^(C1),—SiR^(C1)(OR^(C1))₂, and —Si(OR^(C1))₃, wherein each occurrence ofR^(C1) is independently selected from the group consisting of hydrogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, a nitrogenprotecting group when attached to a nitrogen atom, an oxygen protectinggroup when attached to an oxygen atom, a sulfur protecting group whenattached to a sulfur atom, or two R^(C1) groups are joined to form anoptionally substituted heterocyclic ring or optionally substitutedheteroaryl ring;

R^(q) is independently hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, or anitrogen protecting group;

n is 0, 1, 2, 3, or 4;

L is a bond or an optionally substituted, branched or unbranched C₁₋₆hydrocarbon chain;

R^(D) is any one of Formulae (i-1)-(i-43):

wherein:

each instance of R^(D1) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a),—CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a),—C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a),—C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a),—C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1a), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

each instance of R^(D2) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a),—CH₂N(R^(D2a))₂, —CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a),—C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a),—C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a),—C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and—C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, or two R^(D2a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

each instance of R^(D3) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a),—CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a),—C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a),—C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;

optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring;

R^(D4) is a leaving group selected from the group consisting of —Br,—Cl, —I, and —OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

each instance of X¹ is independently a bond, —C(═O)—, —SO₂—, —NR^(D5)—,optionally substituted alkylene, or optionally substitutedheteroarylene, wherein R^(D5) is hydrogen, C₁₋₆ alkyl, or a nitrogenprotecting group;

each instance of Y is independently O, S, or NR^(D6), wherein R^(D6) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; and

each instance of z and z₁ is independently 0, 1, 2, 3, 4, 5, or 6, asvalency permits.

As generally defined above, Ring A is aryl, arylalkenyl, or heteroaryl.In certain embodiments, Ring A is heteroaryl. In certain embodiments,Ring A is arylalkenyl. In certain embodiments, Ring A is aryl. Ring Amay be substituted with one or more substituents R^(A). The substituentR^(A) may be attached to a carbon atom or heteroatom of Ring A. Incertain embodiments, Ring A is a monocyclic heteroaryl ring. In certainembodiments, Ring A is a bicyclic heteroaryl ring. In certainembodiments, Ring A is a tricyclic heteroaryl ring. In certainembodiments, Ring A is a substituted heteroaryl ring. In certainembodiments, Ring A is an unsubstituted heteroaryl ring. In certainembodiments, Ring A is substituted pyridyl. In certain embodiments, RingA is unsubstituted pyridyl. In certain embodiments, Ring A is aheteroaryl ring fused with one or more carbocyclic, heterocyclic, aryl,or heteroaryl groups wherein the point of attachment is on theheteroaryl ring.

In certain embodiments, Ring A is a 6-membered heteroaryl ring.

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

Ring A of Formula (I) may also be a 5-membered heteroaryl ring. Incertain embodiments, Ring A is a 5-membered heteroaryl ring wherein oneof the five ring carbon atoms is replaced by nitrogen, oxygen, orsulfur.

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, Ring A is a 5-membered heteroaryl ring whereintwo of the five ring carbon atoms are independently replaced bynitrogen, oxygen, or sulfur.

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, Ring A is a 5-membered heteroaryl ring whereinthree of the five ring carbon atoms are independently replaced bynitrogen, oxygen, or sulfur.

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, Ring A is a 5-membered heteroaryl ring whereinfour of the five ring carbon atoms are independently replaced bynitrogen, oxygen, or sulfur.

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, Ring A is bicyclic heteroaryl. In certainembodiments,

is one of the following formulae:

In certain embodiments, Ring A is unsubstituted, and thus k is 0. Incertain embodiments, k is 1. In certain embodiments, k is 2. In certainembodiments, k is 3. In certain embodiments, k is 4. In certainembodiments, k is 5.

In certain embodiments, Ring A is aryl. In certain embodiments, Ring Ais phenyl. In certain embodiments, Ring A is arylalkenyl. In certainembodiments, Ring A is phenylalkenyl. In certain embodiments,

is one of the following formulae:

In certain embodiments, at least one R^(A) is H. In certain embodiments,at least one R^(A) is halogen. In certain embodiments, at least oneR^(A) is F. In certain embodiments, at least one R^(A) is Cl. In certainembodiments, at least one R^(A) is Br. In certain embodiments, at leastone R^(A) is I (iodine). In certain embodiments, at least one R^(A) issubstituted acyl. In certain embodiments, at least one R^(A) isunsubstituted acyl. In certain embodiments, at least one R^(A) isacetyl. In certain embodiments, at least one R^(A) is substituted alkyl.In certain embodiments, at least one R^(A) is unsubstituted alkyl. Incertain embodiments, at least one R^(A) is C₁₋₆ alkyl. In certainembodiments, at least one R^(A) is methyl. In certain embodiments, atleast one R^(A) is ethyl. In certain embodiments, at least one R^(A) ispropyl. In certain embodiments, at least one R^(A) is optionallysubstituted -alkyl-O-alkyl. In certain embodiments, at least one R^(A)is optionally substituted alkylene-O-aryl. In certain embodiments, atleast one R^(A) is optionally substituted alkylene-O-phenyl. In certainembodiments, at least one R^(A) is optionally substitutedalkylene-O-(p-CF₃-phenyl). In certain embodiments, at least one R^(A) isoptionally substituted alkylene-O-(o-CF₃-phenyl). In certainembodiments, at least one R^(A) is optionally substitutedalkylene-O-(m-CF₃-phenyl). In certain embodiments, at least one R^(A) isbutyl. In certain embodiments, at least one R^(A) is substitutedalkenyl. In certain embodiments, at least one R^(A) is unsubstitutedalkenyl. In certain embodiments, at least one R^(A) is substitutedalkynyl. In certain embodiments, at least one R^(A) is unsubstitutedalkynyl. In certain embodiments, at least one R^(A) is substitutedcarbocyclyl. In certain embodiments, at least one R^(A) is unsubstitutedcarbocyclyl. In certain embodiments, at least one R^(A) is substitutedheterocyclyl. In certain embodiments, at least one R^(A) isunsubstituted heterocyclyl. In certain embodiments, at least one R^(A)is substituted aryl. In certain embodiments, at least one R^(A) isunsubstituted aryl. In certain embodiments, at least one R^(A) issubstituted phenyl. In certain embodiments, at least one R^(A) isunsubstituted phenyl. In certain embodiments, at least one R^(A) issubstituted heteroaryl. In certain embodiments, at least one R^(A) isunsubstituted heteroaryl. In certain embodiments, at least one R^(A) issubstituted pyridyl. In certain embodiments, at least one R^(A) isunsubstituted pyridyl. In certain embodiments, at least one R^(A) is—OR^(A1). In certain embodiments, at least one R^(A) is —N(R^(A1))₂. Incertain embodiments, at least one R^(A) is —SR^(A1). In certainembodiments, at least one R^(A) is —OH. In certain embodiments, at leastone R^(A) is —NH₂. In certain embodiments, at least one R^(A) is —SH.

In certain embodiments, when R^(A) is —OR^(A1), —N(R^(A1))₂, or—SR^(A1), at least one R^(A1) is H. In certain embodiments, at least oneR^(A1) is substituted acyl. In certain embodiments, at least one R^(A1)is unsubstituted acyl. In certain embodiments, at least one R^(A1) isacetyl. In certain embodiments, at least one R^(A1) is substitutedalkyl. In certain embodiments, at least one R^(A1) is unsubstitutedalkyl. In certain embodiments, at least one R^(A1) is C₁₋₆ alkyl. Incertain embodiments, at least one R^(A1) is methyl. In certainembodiments, at least one R^(A1) is ethyl. In certain embodiments, atleast one R^(A1) is propyl. In certain embodiments, at least one R^(A1)is butyl. In certain embodiments, at least one R^(A1) is substitutedalkenyl. In certain embodiments, at least one R^(A1) is unsubstitutedalkenyl. In certain embodiments, at least one R^(A1) is substitutedalkynyl. In certain embodiments, at least one R^(A1) is unsubstitutedalkynyl. In certain embodiments, at least one R^(A1) is substitutedcarbocyclyl. In certain embodiments, at least one R^(A1) isunsubstituted carbocyclyl. In certain embodiments, at least one R^(A1)is substituted heterocyclyl. In certain embodiments, at least one R^(A1)is unsubstituted heterocyclyl. In certain embodiments, at least oneR^(A1) is substituted aryl. In certain embodiments, at least one R^(A1)is unsubstituted aryl. In certain embodiments, at least one R^(A1) issubstituted phenyl. In certain embodiments, at least one R^(A1) isunsubstituted phenyl. In certain embodiments, at least one R^(A1) issubstituted heteroaryl. In certain embodiments, at least one R^(A1) isunsubstituted heteroaryl. In certain embodiments, at least one R^(A1) issubstituted pyridyl. In certain embodiments, at least one R^(A1) isunsubstituted pyridyl. In certain embodiments, at least one R^(A1) is anitrogen protecting group when attached to a nitrogen atom. In certainembodiments, at least one R^(A1) is an oxygen protecting group whenattached to an oxygen atom. In certain embodiments, at least one R^(A1)is a sulfur protecting group when attached to a sulfur atom. In certainembodiments, two R^(A1) groups are joined to form a substitutedheterocyclic ring. In certain embodiments, two R^(A1) groups are joinedto form an unsubstituted heterocyclic ring.

In certain embodiments, R^(A) is —N(R^(A1))C(═O)R^(A1). In certainembodiments, R^(A) is —N(R^(A1))C(═O)-alkenyl. In certain embodiments,R^(A) is —N(R^(A1))C(═O)—CH═CH₂. In certain embodiments, R^(A) is—C(═O)N(R^(A1))₂. In certain embodiments, R^(A) is —C(═O)NH₂. In certainembodiments, R^(A) is —C(═O)NHCH₃. In certain embodiments, R^(A) is—C(═O)R^(A1). In certain embodiments, R^(A) is —C(═O)-alkenyl. Incertain embodiments, R^(A) is —C(═O)—CH═CH₂. In certain embodiments,R^(A) is —N(R^(A1))C(═O)N(R^(A1))₂. In certain embodiments, R^(A) is—NHC(═O)N(R^(A1))₂. In certain embodiments, R^(A) is —NHC(═O)NHCH₃. Incertain embodiments, R^(A) is —N(R^(A1))SO₂R^(A1). In certainembodiments, R^(A) is —NHSO₂R^(A1). In certain embodiments, R^(A) is—NHSO₂-alkyl. In certain embodiments, R^(A) is —NHSO₂—CH₃. In certainembodiments, R^(A) is —NHSO₂—C₂H₅. In certain embodiments, R^(A) is—NHSO₂-iPr. In certain embodiments, R^(A) is —NHSO₂—Butyl. In certainembodiments, R^(A) is —NHSO₂-tButyl.

In certain embodiments, R^(A) is heterocyclic ring. In certainembodiments, R^(A) is optionally substituted piperazine. In certainembodiments, R^(A) is N-methyl-piperazine.

In certain embodiments, two R^(A) on Ring A can optionally form anotherring. In certain embodiments, R^(A) is —OR^(A1) and two R^(A1) canoptionally form a heterocyclic ring.

In certain embodiments, R^(A) is substituted C1-6 alkyl; and k is 1. Incertain embodiments, R^(A) is unsubstituted C₁₋₆ alkyl; and k is 1. Incertain embodiments, R^(A) is methyl; and k is 1. In certainembodiments, R^(A) is ethyl; and k is 1. In certain embodiments, R^(A)is propyl; and k is 1. In certain embodiments, R^(A) is butyl; and k is1.

In certain embodiments, R^(A) is halogen; and k is 1. In certainembodiments, R^(A) is F; and k is 1. In certain embodiments, R^(A) isCl; and k is 1. In certain embodiments, R^(A) is Br; and k is 1. Incertain embodiments, R^(A) is I (iodine); and k is 1.

As generally defined above, Ring C is a carbocyclic, heterocyclic, aryl,or heteroaryl ring. Ring C may be substituted with one or moresubstituents R^(C). R^(A) may be a substituent on a carbon atom orheteroatom as valency permits. In certain embodiments, Ring C is acarbocyclic ring. In certain embodiments, Ring C is a monocycliccarbocyclic ring. In certain embodiments, Ring C is a bicycliccarbocyclic ring. In certain embodiments, Ring C is a substitutedcarbocyclic ring. In certain embodiments, Ring C is an unsubstitutedcarbocyclic ring. In certain embodiments, Ring C is a saturatedcarbocyclic ring. In certain embodiments, Ring C is an unsaturatedcarbocyclic ring. In certain embodiments, Ring C is a carbocyclic ringfused with one or more carbocyclic, heterocyclic, aryl, or heteroarylgroups wherein the point of attachment is on the carbocyclic ring.

In certain embodiments, Ring C is a heterocyclic ring. In certainembodiments, Ring C is a monocyclic heterocyclic ring. In certainembodiments, Ring C is a bicyclic heterocyclic ring. In certainembodiments, Ring C is a substituted heterocyclic ring. In certainembodiments, Ring C is an unsubstituted heterocyclic ring. In certainembodiments, Ring C is a saturated heterocyclic ring. In certainembodiments, Ring C is an unsaturated heterocyclic ring. In certainembodiments, Ring C is a heterocyclic ring fused with one or morecarbocyclic, heterocyclic, aryl, or heteroaryl groups wherein the pointof attachment is on the heterocyclic ring.

In certain embodiments, Ring C is an aryl ring. In certain embodiments,Ring C is a monocyclic aryl ring. In certain embodiments, Ring C is abicyclic aryl ring. In certain embodiments, Ring C is a tricyclic arylring. In certain embodiments, Ring C is a substituted aryl ring. Incertain embodiments, Ring C is an unsubstituted aryl ring. In certainembodiments, Ring C is substituted phenyl. In certain embodiments, RingC is unsubstituted phenyl. In certain embodiments, Ring C is an arylring fused with one or more carbocyclic, heterocyclic, aryl, orheteroaryl groups wherein the point of attachment is on the aryl ring.In certain embodiments, Ring C is substituted naphthyl. In certainembodiments, Ring C is unsubstituted naphthyl.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, Ring C is a heteroaryl ring. In certainembodiments, Ring C is a monocyclic heteroaryl ring. In certainembodiments, Ring C is a bicyclic heteroaryl ring. In certainembodiments, Ring C is a tricyclic heteroaryl ring. In certainembodiments, Ring C is a substituted heteroaryl ring. In certainembodiments, Ring C is an unsubstituted heteroaryl ring. In certainembodiments, Ring C is substituted pyridyl. In certain embodiments, RingC is unsubstituted pyridyl. In certain embodiments, Ring C is aheteroaryl ring fused with one or more carbocyclic, heterocyclic, aryl,or heteroaryl groups wherein the point of attachment is on theheteroaryl ring. In certain embodiments, Ring C is a heteroaryl ringfused with a phenyl ring wherein the point of attachment is on thephenyl ring. In certain embodiments, Ring C is substituted indole. Incertain embodiments, Ring C is unsubstituted indole. In certainembodiments, Ring C is substituted isoindole. In certain embodiments,Ring C is unsubstituted isoindole. In certain embodiments, Ring C issubstituted indazole. In certain embodiments, Ring C is unsubstitutedindazole. In certain embodiments, Ring C is substituted benzothiophene.In certain embodiments, Ring C is unsubstituted benzothiophene. Incertain embodiments, Ring C is substituted isobenzothiophene. In certainembodiments, Ring C is unsubstituted isobenzothiophene. In certainembodiments, Ring C is substituted benzofuran. In certain embodiments,Ring C is unsubstituted benzofuran. In certain embodiments, Ring C issubstituted benzoisofuran. In certain embodiments, Ring C isunsubstituted benzoisofuran. In certain embodiments, Ring C issubstituted benzimidazole. In certain embodiments, Ring C isunsubstituted benzimidazole. In certain embodiments, Ring C issubstituted benzoxazole. In certain embodiments, Ring C is unsubstitutedbenzoxazole. In certain embodiments, Ring C is substitutedbenzisoxazole. In certain embodiments, Ring C is unsubstitutedbenzisoxazole. In certain embodiments, Ring C is substitutedbenzothiazole. In certain embodiments, Ring C is unsubstitutedbenzothiazole. In certain embodiments, Ring C is substitutedbenzisothiazole. In certain embodiments, Ring C is unsubstitutedbenzisothiazole. In certain embodiments, Ring C is substitutedbenzotriazole. In certain embodiments, Ring C is unsubstitutedbenzotriazole. In certain embodiments, Ring C is substitutedbenzoxadiazole. In certain embodiments, Ring C is unsubstitutedbenzoxadiazole. In certain embodiments, Ring C is substituted quinoline.In certain embodiments, Ring C is unsubstituted quinoline. In certainembodiments, Ring C is substituted isoquinoline. In certain embodiments,Ring C is unsubstituted isoquinoline. In certain embodiments, Ring C issubstituted cinnoline. In certain embodiments, Ring C is unsubstitutedcinnoline. In certain embodiments, Ring C is substituted quinoxaline. Incertain embodiments, Ring C is unsubstituted quinoxaline. In certainembodiments, Ring C is substituted phthalazine. In certain embodiments,Ring C is unsubstituted phthalazine. In certain embodiments, Ring C issubstituted quinazoline. In certain embodiments, Ring C is unsubstitutedquinazoline.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, Ring C is unsubstituted or substituted with oneor more R^(C). Substituent R^(C) may be attached to a carbon atom orheteroatom as valency permits. In certain embodiments, Ring C isunsubstituted, and thus n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4.

In certain embodiments, at least one R^(C) is H. In certain embodiments,at least one R^(C) is halogen. In certain embodiments, at least oneR^(C) is F. In certain embodiments, at least one R^(C) is Cl. In certainembodiments, at least one R^(C) is Br. In certain embodiments, at leastone R^(C) is I (iodine). In certain embodiments, at least one R^(C) issubstituted acyl. In certain embodiments, at least one R^(C) isunsubstituted acyl. In certain embodiments, at least one R^(C) isacetyl. In certain embodiments, at least one R^(C) is substituted alkyl.In certain embodiments, at least one R^(C) is unsubstituted alkyl. Incertain embodiments, at least one R^(C) is C₁₋₆ alkyl. In certainembodiments, at least one R^(C) is methyl. In certain embodiments, atleast one R^(C) is ethyl. In certain embodiments, at least one R^(C) ispropyl. In certain embodiments, at least one R^(C) is butyl. In certainembodiments, at least one R^(C) is substituted alkenyl. In certainembodiments, at least one R^(C) is unsubstituted alkenyl. In certainembodiments, at least one R^(C) is substituted alkynyl. In certainembodiments, at least one R^(C) is unsubstituted alkynyl. In certainembodiments, at least one R^(C) is substituted carbocyclyl. In certainembodiments, at least one R^(C) is unsubstituted carbocyclyl. In certainembodiments, at least one R^(C) is substituted heterocyclyl. In certainembodiments, at least one R^(C) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(C) is substituted aryl. In certainembodiments, at least one R^(C) is unsubstituted aryl. In certainembodiments, at least one R^(C) is substituted phenyl. In certainembodiments, at least one R^(C) is unsubstituted phenyl. In certainembodiments, at least one R^(C) is substituted heteroaryl. In certainembodiments, at least one R^(C) is unsubstituted heteroaryl. In certainembodiments, at least one R^(C) is substituted pyridyl. In certainembodiments, at least one R^(C) is unsubstituted pyridyl. In certainembodiments, at least one R^(C) is —OR^(C1). In certain embodiments, atleast one R^(C) is —N(R^(C1))₂. In certain embodiments, at least oneR^(C) is —SR^(C1). In certain embodiments, at least one R^(C) is —OH. Incertain embodiments, at least one R^(C) is —NH₂. In certain embodiments,at least one R^(C) is —SH.

In certain embodiments, when R^(C) is —OR^(C1), —N(R^(C1))₂, or—SR^(C1), at least one R^(C1) is H. In certain embodiments, at least oneR^(C1) is substituted acyl. In certain embodiments, at least one R^(C1)is unsubstituted acyl. In certain embodiments, at least one R^(C1) isacetyl. In certain embodiments, at least one R^(C1) is substitutedalkyl. In certain embodiments, at least one R^(C1) is unsubstitutedalkyl. In certain embodiments, at least one R^(C1) is C₁₋₆ alkyl. Incertain embodiments, at least one R^(C1) is methyl. In certainembodiments, at least one R^(C1) is ethyl. In certain embodiments, atleast one R^(C1) is propyl. In certain embodiments, at least one R^(C1)is butyl. In certain embodiments, at least one R^(C1) is substitutedalkenyl. In certain embodiments, at least one R^(C1) is unsubstitutedalkenyl. In certain embodiments, at least one R^(C1) is substitutedalkynyl. In certain embodiments, at least one R^(C1) is unsubstitutedalkynyl. In certain embodiments, at least one R^(C1) is substitutedcarbocyclyl. In certain embodiments, at least one R^(C1) isunsubstituted carbocyclyl. In certain embodiments, at least one R^(C1)is substituted heterocyclyl. In certain embodiments, at least one R^(C1)is unsubstituted heterocyclyl. In certain embodiments, at least oneR^(C1) is substituted aryl. In certain embodiments, at least one R^(C1)is unsubstituted aryl. In certain embodiments, at least one R^(C1) issubstituted phenyl. In certain embodiments, at least one R^(C1) isunsubstituted phenyl. In certain embodiments, at least one R^(C1) issubstituted heteroaryl. In certain embodiments, at least one R^(C1) isunsubstituted heteroaryl. In certain embodiments, at least one R^(C1) issubstituted pyridyl. In certain embodiments, at least one R^(C1) isunsubstituted pyridyl. In certain embodiments, at least one R^(C1) is anitrogen protecting group when attached to a nitrogen atom. In certainembodiments, at least one R^(C1) is an oxygen protecting group whenattached to an oxygen atom. In certain embodiments, at least one R^(C1)is a sulfur protecting group when attached to a sulfur atom. In certainembodiments, two R^(C1) groups are joined to form a substitutedheterocyclic ring. In certain embodiments, two R^(C1) groups are joinedto form an unsubstituted heterocyclic ring.

In certain embodiments, R^(C) is substituted C₁₋₆ alkyl; and n is 1. Incertain embodiments, R^(C) is unsubstituted C1-6 alkyl; and n is 1. Incertain embodiments, R^(C) is methyl; and n is 1. In certainembodiments, R^(C) is ethyl; and n is 1. In certain embodiments, R^(C)is propyl; and n is 1. In certain embodiments, R^(C) is butyl; and n is1.

In certain embodiments, R^(C) is halogen; and n is 1. In certainembodiments, R^(C) is F; and n is 1. In certain embodiments, R^(C) isC1; and n is 1. In certain embodiments, R^(C) is Br; and n is 1. Incertain embodiments, R^(C) is I (iodine); and n is 1.

Linker L is a divalent linker moiety. L may contain 0-6 carbon atoms inthe backbone of L. In certain embodiments, L contains 0-4 carbon atomsin the backbone of L. In certain embodiments, L contains 0-3 carbonatoms in the backbone of L. In certain embodiments, L contains 0-2carbon atoms in the backbone of L. L may be saturated or unsaturated. Lmay be substituted or unsubstituted. L may be branched or unbranched. Incertain embodiments, L is a bond directly connecting Ring C and R^(D).In certain embodiments, L is a single bond. In certain embodiments, L isa C₁ hydrocarbon chain substituted with one or more R^(L) groups. Incertain embodiments, L is —CH₂—. In certain embodiments, L is a C₂hydrocarbon chain substituted with one or more R^(L) groups. In certainembodiments, L is —(CH₂)₂—. In certain embodiments, L is trans-CH═CH—.In certain embodiments, L is cis-CH═CH—. In certain embodiments, L is—C—C—. In certain embodiments, L is a C₃ hydrocarbon chain substitutedwith one or more R^(L) groups. In certain embodiments, L is —(CH₂)₃—. Incertain embodiments, L is a C₄ hydrocarbon chain substituted with one ormore R^(L) groups. In certain embodiments, L is —(CH₂)₄—. In certainembodiments, L is a C₅ hydrocarbon chain substituted with one or moreR^(L) groups. In certain embodiments, L is —(CH₂)₅—. In certainembodiments, L is a C₆ hydrocarbon chain substituted with one or moreR^(L) groups. In certain embodiments, L is —(CH₂)₆—. Each occurrence ofR^(L) is independently selected from the group consisting of hydrogen,halogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, —CN,—C(═NR^(L1))R^(L1), —C(═NR^(L1))OR^(L1), —C(═NR^(L1))SR^(L1),—C(═NR^(L1))N(R^(L1))₂, —C(═S)R^(L1), —C(═S)OR^(L1), —C(═S)SR^(L1),—C(═S)N(R^(L1))₂, —NO₂, —N₃, —N(R^(L1))₃ ⁺F⁻, —N(R^(L1))₃ ⁺Cl⁻,—N(R^(L1))₃ ⁺Br⁻, —N(R^(L1))₃ ⁺I⁻, —N(OR^(L1))R^(L1),—NR^(L1)C(═O)R^(L1), —NR^(L1)C(═O)OR^(L1), —NR^(L1)C(═O)SR^(L1),—NR^(L1)C(═O)N(R^(L1))₂, —NR^(L1)C(═S)R^(L1), —NR^(L1)C(═S)OR^(L1),—NR^(L1)C(═S)SR^(L1), —NR^(L1)C(═S)N(R^(L1))₂,—NR^(L1)C(═NR^(L1))R^(L1), —NR^(L1)C(═NR^(L1))OR^(L1), —NR^(L1)C(═NR^(L1))SR^(L1), —NR^(L1)C(═NR^(L1))N(R^(L1))₂, —NR^(L1)S(═O)₂R^(L1), —NR^(L1)S(═O)₂OR^(L1), —NR^(L1) S(═O)₂SR^(L1), —NR^(L1)S(═O)₂N(R^(L1))₂, —NR^(L1)S(═O)R^(L1), —NR^(L1)S(═O)OR^(L1), —NR^(L1)S(═O)SR^(L1), —NR^(L1)S(═O)N(R^(L1))₂, —NR^(L1)P(═O), —NR^(L1)P(═O)₂,—NR^(L1)(═O)(R^(L1))₂, NR^(L1)P(═O)R^(L1)(OR^(L1)),—NR^(L1)P(═O)(OR^(L1))₂, —OC(═O)R^(L1), —OC(═O)OR^(L1), —OC(═O)SR^(L1),—OC(═O)N(R^(L1))₂, —OC(═NR^(L1))R^(L1), —OC(═NR^(L1))OR^(L1),—OC(═NR^(L1))N(R^(L1))₂, —OC(═S)R^(L1), —OC(═S)OR^(L1), —OC(═S)SR^(L1),—OC(═S)N(R^(L1))₂, —ON(R^(L1))₂, —OS(═O)R^(L1), —OS(═O)OR^(L1),—OS(═O)SR^(L1), —OS(═O)N(R^(L1))₂, —OS(═O)₂R^(L1), —OS(═O)₂OR^(L1),—OS(═O)₂SR^(L1), —OS(═O)₂N(R^(L1))₂, —OP(═O)₂, —OP(═O)(R^(L1))₂,—OP(═O)R^(L1)(OR^(L1)), —OP(═O)(OR^(L1))₂, —OP(═O), —OP(R^(L1))₂,—OPR^(L1)(OR^(L1)), —OP(OR^(L1))₂, —OSi(R^(L1))₃, —OSi(R^(L1))₂OR^(L1),—OSi(R^(L1))(OR^(L1))₂, —OSi(OR^(L1))₃, —SSR^(L1), —S(═O)R^(L1),—S(═O)OR^(L1), —S(═O)N(R^(L1))₂, —S(═O)₂R^(L1), —S(═O)₂OR^(L1),—S(═O)₂N(R^(L1))₂, —SC(═O)R^(L1), —SC(═O)OR^(L1), —SC(═O)SR^(L1),—SC(═O)N(R^(L1))₂, —SC(═S)R^(L1), —SC(═S)OR^(L1), —SC(═S)SR^(L1),—SC(═S)N(R^(L1))₂, —P(R^(L1))₂, —PR^(L1)(OR^(L1)), —P(OR^(L1))₂, —P(═O),—P(═O)(R^(L1))₂, —P(═O)(OR^(L1))₂, —P(═O)R^(L1)(OR^(L1)), —P(═O)₂,—B(R^(L1))₂, —B(OR^(L1))₂, —BR^(L1)(OR^(L1)), —Si(R^(L1))₃,—Si(R^(L1))₂OR^(L1), —SiR^(L1)(OR^(L1))₂, and —Si(OR^(L1))₃, whereineach occurrence of R^(L1) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(L1) groups are joined to form an optionally substituted heterocyclicring.

Each of R^(j1), R^(j2), R^(j3) is an independent substituent on thedouble bond in Formula (II). In certain embodiments, each of R^(j1),R^(j2), R^(j3) is independently hydrogen or substituted C₁₋₆ alkyl. Incertain embodiments, each of R^(j1), R^(j2), R^(j3) is independentlyhydrogen. In certain embodiments, each of R^(j1), R^(j2), R^(j3) isindependently unsubstituted C1-6 alkyl. In certain embodiments, each ofR^(j1), R^(j2), R^(j3) is independently methyl, ethyl, propyl, butyl,pentyl, or hexyl. In certain embodiments, each of R^(j1), R^(j2), R^(j3)is independently halogen. In certain embodiments, In certainembodiments, each of R^(j1), R^(j2), R^(j3) is independently F. Incertain embodiments, In certain embodiments, each of R^(j1), R^(j2),R^(j3) is independently Cl. In certain embodiments, each of R^(j1),R^(j2), R^(j3) is independently Br. In certain embodiments, each ofR^(j1), R^(j2), R^(j3) is independently I.

As generally defined herein, R^(q) is independently hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, or a nitrogen protecting group. In certainembodiments, R^(q) is hydrogen. In some embodiments, R^(q) is optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, or optionally substituted carbocyclyl. In certainembodiments, R^(q) is optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, oroptionally substituted C₃₋₆ carbocyclyl. In certain embodiments, R^(q)is optionally substituted C1-6 alkyl. In certain embodiments, R^(q) issubstituted C1-6 alkyl. In certain embodiments, R^(q) is unsubstitutedC1-6 alkyl. In certain embodiments, R^(q) is methyl, ethyl, propyl,butyl, pentyl, or hexyl. In certain embodiments, R^(q) is isopropyl,isobutyl, or isoamyl. In certain embodiments, R^(q) is isobutyl. Incertain embodiments, R^(q) is tert-butyl. In certain embodiments, R^(q)is a nitrogen protecting group.

R^(D) is a substituent on Ring C through linker L. In certainembodiments, R^(D) includes a Michael acceptor moiety. This Michaelacceptor moiety may react with a cysteine residue of a host factor toallow covalent attachment of the compound to the host factor. In certainembodiments, the covalent attachment is irreversible, and viral entryand/or infection is reduced. In certain embodiments, the covalentattachment is reversible, and viral entry and/or infection is reduced.

In certain embodiments, R^(D) is a group selected from the groupconsisting of:

In certain embodiments, at least one R^(D1) is H. In certainembodiments, at least one R^(D1) is halogen. In certain embodiments, atleast one R^(D1) is F. In certain embodiments, at least one R^(D1) isCl. In certain embodiments, at least one R^(D1) is Br. In certainembodiments, at least one R^(D1) is I (iodine). In certain embodiments,at least one R^(D1) is substituted acyl. In certain embodiments, atleast one R^(D1) is unsubstituted acyl. In certain embodiments, at leastone R^(D1) is acetyl. In certain embodiments, at least one R^(D1) issubstituted alkyl. In certain embodiments, at least one R^(D1) isunsubstituted alkyl. In certain embodiments, at least one R^(D1) is C₁₋₆alkyl. In certain embodiments, at least one R^(D1) is methyl. In certainembodiments, at least one R^(D1) is ethyl. In certain embodiments, atleast one R^(D1) is propyl. In certain embodiments, at least one R^(D1)is butyl. In certain embodiments, at least one R^(D1) is substitutedalkenyl. In certain embodiments, at least one R^(D1) is unsubstitutedalkenyl. In certain embodiments, at least one R^(D1) is substitutedalkynyl. In certain embodiments, at least one R^(D1) is unsubstitutedalkynyl. In certain embodiments, at least one R^(D1) is substitutedcarbocyclyl. In certain embodiments, at least one R^(D1) isunsubstituted carbocyclyl. In certain embodiments, at least one R^(D1)is substituted heterocyclyl. In certain embodiments, at least one R^(D1)is unsubstituted heterocyclyl. In certain embodiments, at least oneR^(D1) is substituted aryl. In certain embodiments, at least one R^(D1)is unsubstituted aryl. In certain embodiments, at least one R^(D1) issubstituted phenyl. In certain embodiments, at least one R^(D1) isunsubstituted phenyl. In certain embodiments, at least one R^(D1) issubstituted heteroaryl. In certain embodiments, at least one R^(D1) isunsubstituted heteroaryl. In certain embodiments, at least one R^(D1) issubstituted pyridyl. In certain embodiments, at least one R^(D1) isunsubstituted pyridyl. In certain embodiments, at least one R^(D1) is—OR^(D1a). In certain embodiments, at least one R^(D1) is —N(R^(D1a))₂.In certain embodiments, at least one R^(D1) is —SR^(D1a)In certainembodiments, at least one R^(D1) is —OH. In certain embodiments, atleast one R^(D1) is —NH₂. In certain embodiments, at least one R^(D1) is—SH. In certain embodiments, at least one R^(D1) is —CH₂OR^(D1a). Incertain embodiments, at least one R^(D1) is —CH₂N(R^(D1a))₂. In certainembodiments, at least one R^(D1) is —CH₂SR^(D1a). In certainembodiments, at least one R^(D1) is —CH₂OH. In certain embodiments, atleast one R^(D1) is —CH₂NH₂. In certain embodiments, at least one R^(D1)is —CH₂SH.

In certain embodiments, at least one R^(D1a) is H. In certainembodiments, at least one R^(D1a) is substituted acyl. In certainembodiments, at least one R^(D1a) is unsubstituted acyl. In certainembodiments, at least one R^(D1a) is acetyl. In certain embodiments, atleast one R^(D1a) is substituted alkyl. In certain embodiments, at leastone R^(D1a) is unsubstituted alkyl. In certain embodiments, at least oneR^(D1a) is C₁₋₆ alkyl. In certain embodiments, at least one R^(D1a) ismethyl. In certain embodiments, at least one R^(D1a) is ethyl. Incertain embodiments, at least one R^(D1a) is propyl. In certainembodiments, at least one R^(D1a) is butyl. In certain embodiments, atleast one R^(D1a) is substituted alkenyl. In certain embodiments, atleast one R^(D1a) is unsubstituted alkenyl. In certain embodiments, atleast one R^(D1a) is substituted alkynyl. In certain embodiments, atleast one R^(D1a) is unsubstituted alkynyl. In certain embodiments, atleast one R^(D1a) is substituted carbocyclyl. In certain embodiments, atleast one R^(D1a) is unsubstituted carbocyclyl. In certain embodiments,at least one R^(D1a) is substituted heterocyclyl. In certainembodiments, at least one R^(D1a) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(D1a) is substituted aryl. Incertain embodiments, at least one R^(D1a) is unsubstituted aryl. Incertain embodiments, at least one R^(D1a) is substituted phenyl. Incertain embodiments, at least one R^(D1a) is unsubstituted phenyl. Incertain embodiments, at least one R^(D1a) is substituted heteroaryl. Incertain embodiments, at least one R^(D1a) is unsubstituted heteroaryl.In certain embodiments, at least one R^(D1a) is substituted pyridyl. Incertain embodiments, at least one R^(D1a) is unsubstituted pyridyl. Incertain embodiments, at least one R^(D1a) is a nitrogen protecting groupwhen attached to a nitrogen atom. In certain embodiments, at least oneR^(D1a) is an oxygen protecting group when attached to an oxygen atom.In certain embodiments, at least one R^(D1a) is a sulfur protectinggroup when attached to a sulfur atom. In certain embodiments, twoR^(D1a) groups are joined to form a substituted heterocyclic ring. Incertain embodiments, two R^(D1a) groups are joined to form anunsubstituted heterocyclic ring.

In certain embodiments, at least one R^(D2) is H. In certainembodiments, at least one R^(D2) is halogen. In certain embodiments, atleast one R^(D2) is F. In certain embodiments, at least one R^(D2) isCl. In certain embodiments, at least one R^(D2) is Br. In certainembodiments, at least one R^(D2) is I (iodine). In certain embodiments,at least one R^(D2) is substituted acyl. In certain embodiments, atleast one R^(D2) is unsubstituted acyl. In certain embodiments, at leastone R^(D2) is acetyl. In certain embodiments, at least one R^(D2) issubstituted alkyl. In certain embodiments, at least one R^(D2) isunsubstituted alkyl. In certain embodiments, at least one R^(D2) is C₁₋₆alkyl. In certain embodiments, at least one R^(D2) is methyl. In certainembodiments, at least one R^(D2) is ethyl. In certain embodiments, atleast one R^(D2) is propyl. In certain embodiments, at least one R^(D2)is butyl. In certain embodiments, at least one R^(D2) is substitutedalkenyl. In certain embodiments, at least one R^(D2) is unsubstitutedalkenyl. In certain embodiments, at least one R^(D2) is substitutedalkynyl. In certain embodiments, at least one R^(D2) is unsubstitutedalkynyl. In certain embodiments, at least one R^(D2) is substitutedcarbocyclyl. In certain embodiments, at least one R^(D2) isunsubstituted carbocyclyl. In certain embodiments, at least one R^(D2)is substituted heterocyclyl. In certain embodiments, at least one R^(D2)is unsubstituted heterocyclyl. In certain embodiments, at least oneR^(D2) is substituted aryl. In certain embodiments, at least one R^(D2)is unsubstituted aryl. In certain embodiments, at least one R^(D2) issubstituted phenyl. In certain embodiments, at least one R^(D2) isunsubstituted phenyl. In certain embodiments, at least one R^(D2) issubstituted heteroaryl. In certain embodiments, at least one R^(D2) isunsubstituted heteroaryl. In certain embodiments, at least one R^(D2) issubstituted pyridyl. In certain embodiments, at least one R^(D2) isunsubstituted pyridyl. In certain embodiments, at least one R^(D2) is—OR^(D2a). In certain embodiments, at least one R^(D2) is —N(R^(D2a))₂.In certain embodiments, at least one R^(D2) is —SR^(D2a). In certainembodiments, at least one R^(D2) is —OH. In certain embodiments, atleast one R^(D2) is —NH₂. In certain embodiments, at least one R^(D2) is—SH. In certain embodiments, at least one R^(D2) is —CH₂OR^(D2a). Incertain embodiments, at least one R^(D2) is —CH₂N(R^(D2a))₂. In certainembodiments, at least one R^(D2) is —CH₂SR^(D1a). In certainembodiments, at least one R^(D2) is —CH₂OH. In certain embodiments, atleast one R^(D2) is —CH₂NH₂. In certain embodiments, at least one R^(D2)is —CH₂SH.

In certain embodiments, at least one R^(D2a) is H. In certainembodiments, at least one R^(D2a) is substituted acyl. In certainembodiments, at least one R^(D2a) is unsubstituted acyl. In certainembodiments, at least one R^(D2a) is acetyl. In certain embodiments, atleast one R^(D2a) is substituted alkyl. In certain embodiments, at leastone R^(D2a) is unsubstituted alkyl. In certain embodiments, at least oneR^(D2a) is C₁₋₆ alkyl. In certain embodiments, at least one R^(D2a) ismethyl. In certain embodiments, at least one R^(D2a) is ethyl. Incertain embodiments, at least one R^(D2a) is propyl. In certainembodiments, at least one R^(D2a) is butyl. In certain embodiments, atleast one R^(D2a) is substituted alkenyl. In certain embodiments, atleast one R^(D2a) is unsubstituted alkenyl. In certain embodiments, atleast one R^(D2a) is substituted alkynyl. In certain embodiments, atleast one R^(D2a) is unsubstituted alkynyl. In certain embodiments, atleast one R^(D2a) is substituted carbocyclyl. In certain embodiments, atleast one R^(D2a) is unsubstituted carbocyclyl. In certain embodiments,at least one R^(D2a) is substituted heterocyclyl. In certainembodiments, at least one R^(D2a) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(D2a) is substituted aryl. Incertain embodiments, at least one R^(D2a) is unsubstituted aryl. Incertain embodiments, at least one R^(D2a) is substituted phenyl. Incertain embodiments, at least one R^(D2a) is unsubstituted phenyl. Incertain embodiments, at least one R^(D2a) is substituted heteroaryl. Incertain embodiments, at least one R^(D2a) is unsubstituted heteroaryl.In certain embodiments, at least one R^(D2a) is substituted pyridyl. Incertain embodiments, at least one R^(D2a) is unsubstituted pyridyl. Incertain embodiments, at least one R^(D2a) is a nitrogen protecting groupwhen attached to a nitrogen atom. In certain embodiments, at least oneR^(D2a) is an oxygen protecting group when attached to an oxygen atom.In certain embodiments, at least one R^(D2a) is a sulfur protectinggroup when attached to a sulfur atom. In certain embodiments, twoR^(D2a) groups are joined to form a substituted heterocyclic ring. Incertain embodiments, two R^(D2a) groups are joined to form anunsubstituted heterocyclic ring.

In certain embodiments, at least one R^(D3) is H. In certainembodiments, at least one R^(D3) is halogen. In certain embodiments, atleast one R^(D3) is F. In certain embodiments, at least one R^(D3) isCl. In certain embodiments, at least one R^(D3) is Br. In certainembodiments, at least one R^(D3) is I (iodine). In certain embodiments,at least one R^(D3) is substituted acyl. In certain embodiments, atleast one R^(D3) is unsubstituted acyl. In certain embodiments, at leastone R^(D3) is acetyl. In certain embodiments, at least one R^(D3) issubstituted alkyl. In certain embodiments, at least one R^(D3) isunsubstituted alkyl. In certain embodiments, at least one R^(D3) is C₁₋₆alkyl. In certain embodiments, at least one R^(D3) is methyl. In certainembodiments, at least one R^(D3) is ethyl. In certain embodiments, atleast one R^(D3) is propyl. In certain embodiments, at least one R^(D3)is butyl. In certain embodiments, at least one R^(D3) is substitutedalkenyl. In certain embodiments, at least one R^(D3) is unsubstitutedalkenyl. In certain embodiments, at least one R^(D3) is substitutedalkynyl. In certain embodiments, at least one R^(D3) is unsubstitutedalkynyl. In certain embodiments, at least one R^(D3) is substitutedcarbocyclyl. In certain embodiments, at least one R^(D3) isunsubstituted carbocyclyl. In certain embodiments, at least one R^(D3)is substituted heterocyclyl. In certain embodiments, at least one R^(D3)is unsubstituted heterocyclyl. In certain embodiments, at least oneR^(D3) is substituted aryl. In certain embodiments, at least one R^(D3)is unsubstituted aryl. In certain embodiments, at least one R^(D3) issubstituted phenyl. In certain embodiments, at least one R^(D3) isunsubstituted phenyl. In certain embodiments, at least one R^(D3) issubstituted heteroaryl. In certain embodiments, at least one R^(D3) isunsubstituted heteroaryl. In certain embodiments, at least one R^(D3) issubstituted pyridyl. In certain embodiments, at least one R^(D3) isunsubstituted pyridyl. In certain embodiments, at least one R^(D3) is—OR^(D3a). In certain embodiments, at least one R^(D3) is —N(R^(D3a))₂.In certain embodiments, at least one R^(D3) is —SR^(D3a). In certainembodiments, at least one R^(D) is —OH. In certain embodiments, at leastone R^(D3) is —NH₂. In certain embodiments, at least one R^(D3) is —SH.In certain embodiments, at least one R^(D3) is —CH₂OR^(D3a). In certainembodiments, at least one R^(D) is —CH₂N(R^(D3a))₂. In certainembodiments, at least one R^(D3) is —CH₂SR^(D3a). In certainembodiments, at least one R^(D3) is —CH₂OH. In certain embodiments, atleast one R^(D3) is —CH₂NH₂. In certain embodiments, at least one R^(D3)is —CH₂SH.

In certain embodiments, at least one R^(D3a) is H. In certainembodiments, at least one R^(D3a) is substituted acyl. In certainembodiments, at least one R^(D3a) is unsubstituted acyl. In certainembodiments, at least one R^(D3a) is acetyl. In certain embodiments, atleast one R^(D3a) is substituted alkyl. In certain embodiments, at leastone R^(D3a) is unsubstituted alkyl. In certain embodiments, at least oneR^(D3a) is C₁₋₆ alkyl. In certain embodiments, at least one R^(D3a) ismethyl. In certain embodiments, at least one R^(D3a) is ethyl. Incertain embodiments, at least one R^(D3a) is propyl. In certainembodiments, at least one R^(D3a) is butyl. In certain embodiments, atleast one R^(D3a) is substituted alkenyl. In certain embodiments, atleast one R^(D3a) is unsubstituted alkenyl. In certain embodiments, atleast one R^(D3a) is substituted alkynyl. In certain embodiments, atleast one R^(D3a) is unsubstituted alkynyl. In certain embodiments, atleast one R^(D3a) is substituted carbocyclyl. In certain embodiments, atleast one R^(D3a) is unsubstituted carbocyclyl. In certain embodiments,at least one R^(D3a) is substituted heterocyclyl. In certainembodiments, at least one R^(D3a) is unsubstituted heterocyclyl. Incertain embodiments, at least one R^(D3a) is substituted aryl. Incertain embodiments, at least one R^(D3a) is unsubstituted aryl. Incertain embodiments, at least one R^(D3a) is substituted phenyl. Incertain embodiments, at least one R^(D3a) is unsubstituted phenyl. Incertain embodiments, at least one R^(D3a) is substituted heteroaryl. Incertain embodiments, at least one R^(D3a) is unsubstituted heteroaryl.In certain embodiments, at least one R^(D3a) is substituted pyridyl. Incertain embodiments, at least one R^(D3a) is unsubstituted pyridyl. Incertain embodiments, at least one R^(D3a) is a nitrogen protecting groupwhen attached to a nitrogen atom. In certain embodiments, at least oneR^(D3a) is an oxygen protecting group when attached to an oxygen atom.In certain embodiments, at least one R^(D3a) is a sulfur protectinggroup when attached to a sulfur atom. In certain embodiments, twoR^(D3a) groups are joined to form a substituted heterocyclic ring. Incertain embodiments, two R^(D3a) groups are joined to form anunsubstituted heterocyclic ring.

In certain embodiments, R^(m) is a leaving group. In certainembodiments, R^(D4) is Cl. In certain embodiments, R^(D4) is Br. Incertain embodiments, R^(D4) is I (iodine). In certain embodiments,R^(D4) is —OS(═O)_(w)R^(D4a). In certain embodiments, R^(D4) is —OMs. Incertain embodiments, R^(D4) is —OTf. In certain embodiments, R^(D4) is—OTs.

In certain embodiments, w is 1. In certain embodiments, w is 2.

In certain embodiments, R^(D4a) is substituted alkyl. In certainembodiments, R^(D4a) is unsubstituted alkyl. In certain embodiments,R^(D4a) is substituted alkenyl. In certain embodiments, R^(D4a) isunsubstituted alkenyl. In certain embodiments, R^(D4a) is substitutedalkynyl. In certain embodiments, R^(D4a) is unsubstituted alkynyl. Incertain embodiments, R^(D4a) is substituted carbocyclyl. In certainembodiments, R^(D4a) is unsubstituted carbocyclyl. In certainembodiments, R^(D4a) is substituted heterocyclyl. In certainembodiments, R^(D4a) is unsubstituted heterocyclyl. In certainembodiments, R^(D4a) is substituted aryl. In certain embodiments,R^(D4a) is unsubstituted aryl. In certain embodiments, R^(D4a) issubstituted heteroaryl. In certain embodiments, R^(D4a) is unsubstitutedheteroaryl.

In certain embodiments, R^(D5) is H. In certain embodiments, R^(D5) issubstituted alkyl. In certain embodiments, R^(D5) is unsubstitutedalkyl. In certain embodiments, R^(D5) is C₁₋₆ alkyl. In certainembodiments, R^(D5) is methyl. In certain embodiments, R^(D5) is ethyl.In certain embodiments, R^(D5) is propyl. In certain embodiments, R^(D5)is butyl. In certain embodiments, R^(D5) is a nitrogen protecting group.In certain embodiments, R^(D5) is BOC. In certain embodiments, R^(D5) isCbz. In certain embodiments, R^(D5) is Fmoc. In certain embodiments,R^(D5) is Bn.

In certain embodiments, a is 1. In certain embodiments, a is 2.

In certain embodiments, Y is —O—. In certain embodiments, Y is ═O. Incertain embodiments, Y is —S—. In certain embodiments, Y is ═S. Incertain embodiments, Y is —NR^(D6-), wherein R^(D6) is hydrogen, C₁₋₆alkyl, or a nitrogen protecting group. In certain embodiments, Y is—NH—. In certain embodiments, Y is —NCH₃—. In certain embodiments, Y is—N(BOC)—. In certain embodiments, Y is —N(Fmoc)-. In certainembodiments, Y is —N(Cbz)-. In certain embodiments, Y is —N(Bn)-. Incertain embodiments, Y is ═NR^(D6), wherein R^(D6) is hydrogen, C₁₋₆alkyl, or a nitrogen protecting group. In certain embodiments, Y is ═NH.In certain embodiments, Y is ═NCH₃. In certain embodiments, Y is =NTs.In certain embodiments, Y is =NBn. In certain embodiments, Y is═NCH(Ph)₂.

As used herein, each of z and z1 is independently 0, 1, 2, 3, 4, 5, or6, as valency permits. In certain embodiments, z is 0. In certainembodiments, z is 1. In certain embodiments, z is 2. In certainembodiments, z is 3. In certain embodiments, z is 4. In certainembodiments, z is 5. In certain embodiments, z is 6. In certainembodiments, z1 is 0. In certain embodiments, z1 is 1. In certainembodiments, z1 is 2. In certain embodiments, z1 is 3. In certainembodiments, z1 is 4. In certain embodiments, z1 is 5. In certainembodiments, z1 is 6.

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is a group of Formula (i-1), (i-3), or(i-20):

wherein each instance of X¹ is bond or NR^(D5), Y is independently O, S,or NR^(D6), and R^(D1), R^(D2), and R^(D3) are as defined herein. Incertain embodiments, X¹ is a bond. In certain embodiments, X¹ isNR^(D5). In certain embodiments, Y is O. In certain embodiments, R^(D1)is hydrogen. In certain embodiments, R^(D1) is —CN. In certainembodiments, R^(D2) is hydrogen. In certain embodiments, R^(D3) ishydrogen. In certain embodiments, R^(D2) is —CH₂N(R^(D2a))₂, and R^(D3)is hydrogen. In certain embodiments, R^(D2) is —CH₂N(R^(D3a))₂, andR^(D3) is hydrogen. In certain embodiments, R^(D2) and R^(D3) arehydrogen. In certain embodiments, R^(D1), R^(D2) and R^(D3) arehydrogen.

In certain embodiments, R^(D) is a group of Formula (i-19), (i-17), or(i-18):

wherein Y is independently O, S, or NR^(D6); and R^(D1), R^(D2), andR^(D3) are as defined herein. In certain embodiments, Y is O. In certainembodiments, R^(D1) is hydrogen. In certain embodiments, R^(D2) ishydrogen. In certain embodiments, R^(D2) is —CN. In certain embodiments,R^(D3) is substituted or unsubstituted alkyl.

In certain embodiments, R^(D) is a group of Formula (i-7) or (i-8):

wherein Y is independently O, S, or NR^(D6); and R^(D1), R^(D2), andR^(D3) are as defined herein. In certain embodiments, Y is O. In certainembodiments, R^(D1) is hydrogen. In certain embodiments, R^(D2) ishydrogen. In certain embodiments, R^(D3) is hydrogen.

In certain embodiments, R^(D) is a group of Formula (i-13) or (i-14):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); and R^(D1) and R^(D2) are as defined herein. In certainembodiments, X¹ is a bond. In certain embodiments, X¹ is NR^(D5). Incertain embodiments, Y is O. In certain embodiments, R^(D1) is hydrogen.In certain embodiments, R^(D1) is halogen, e.g., —F or —Cl. In certainembodiments, R^(D2) is hydrogen. In certain embodiments, R^(D2) ishalogen, e.g., —F or —Cl.

In certain embodiments, R^(D) is a group of Formula (i-11) or (i-12):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); z is 0, 1, 2, 3, 4, 5, or 6; and R^(D1) is as definedherein. In certain embodiments, X¹ is a bond. In certain embodiments, X¹is NR^(D5). In certain embodiments, Y is O. In certain embodiments z is0 or 1. In certain embodiments, R^(D1) is substituted or unsubstitutedalkyl.

In certain embodiments, R^(D) is a group of Formula (i-10), (i-16), or(i-9):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); z is 0, 1, 2, 3, 4, 5, or 6; and R^(D4) is a leaving groupselected from the group consisting of —Br, —Cl, —I, and—OS(═O)_(w)R^(D4a), wherein w is 1 or 2. In certain embodiments, X¹ is abond. In certain embodiments, X¹ is NR^(D5). In certain embodiments, Yis O. In certain embodiments, z is 0. In certain embodiments, z is 1.

In certain embodiments, R^(D) is a group of Formula (i-4) or (i-5):

wherein each instance of X¹ is bond or NR^(D5); and R^(D1) is as definedherein. In certain embodiments, X¹ is a bond. In certain embodiments, X¹is NR^(D5). In certain embodiments, R^(D1) is hydrogen.

In certain embodiments, R^(D) is a group of Formula (i-6):

wherein each instance of X¹ is bond or NR^(D5); Y is independently O, S,or NR^(D6); and R^(D1) is as defined herein. In certain embodiments, X¹is a bond. In certain embodiments, X¹ is NR^(D5). In certainembodiments, Y is O. In certain embodiments, R^(D1) is hydrogen.

In certain embodiments, R^(D) is a group of Formula (i-21)-(i-32),(i-39) and (i-40), wherein each instance of X¹ is independently a bond,—C(═O)—, —SO₂—, —NR^(D5), optionally substituted alkylene, or optionallysubstituted heteroarylene, wherein R^(D5) is hydrogen, C₁₋₆ alkyl, or anitrogen protecting group; Y is independently O, S, or NR^(D6); andR^(D1), R^(D2), and R^(D3) are as defined herein. In certainembodiments, X¹ is a bond. In certain embodiments, X¹ is —C(═O)—. Incertain embodiments, X¹ is —SO₂—. In certain embodiments, X¹ is—NR^(D5). In certain embodiments, X¹ is optionally substituted alkylene.In certain embodiments, X¹ is substituted alkylene. In certainembodiments, X¹ is unsubstituted alkylene. In certain embodiments, Y isO. In certain embodiments, Y is S. In certain embodiments, Y is NR^(D6).In certain embodiments, R^(D1) is hydrogen. In certain embodiments,R^(D2) is hydrogen. In certain embodiments, R^(D2) is —CN. In certainembodiments, R^(D3) is substituted or unsubstituted alkyl.

In certain embodiments, R^(D) is a group of Formulae (i-33) and(i-36)-(i-38), wherein each instance of X¹ is independently a bond,—C(═O)—, —SO₂—, —NR^(D), optionally substituted alkylene, or optionallysubstituted heteroarylene, wherein R^(D5) is hydrogen, C₁₋₆ alkyl, or anitrogen protecting group; and R^(D1) is as defined herein. In certainembodiments, X¹ is optionally substituted heteroarylene. In certainembodiments, X¹ is optionally substituted heteroarylene. In certainembodiments, X¹ is optionally substituted five-membered heteroarylene.In certain embodiments, X¹ is optionally substituted five-memberedheteroarylene with at least one S, O, and N. In certain embodiments, X¹is optionally substituted six-membered heteroarylene. In certainembodiments, X¹ is optionally substituted six-membered heteroarylenewith at least one S, O, and N.

In certain embodiments, R^(D) is a group of Formula (i-34), wherein eachinstance of z and R^(D1) are as defined herein. In certain embodiments,R^(D1) is halogen. In certain embodiments, R^(D1) is F. In certainembodiments, R^(D1) is Cl. In certain embodiments, R^(D1) is Br. Incertain embodiments, R^(D1) is I In certain embodiments, R^(D1) is CN.In certain embodiments, R^(D1) is NO₂.

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is

In certain embodiments, R^(D) is selected from one of the followingformulae:

In certain embodiments, the invention provides intermediates of formulae(a)-(c) or salts thereof to prepare formulae (I)-(III), wherein R^(D),L, Ring C, R^(C), n, R^(j1), R^(j2), R^(j3), R^(q) are as defined above;and M is halogen. In certain embodiments, M is F. In certainembodiments, M is Cl. In certain embodiments, M is Br. In certainembodiments, M is I.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

R^(D5) and one R^(C) may be joined to form a substituted heteroarylring. R^(D5) and one R^(C), may also be joined to form an unsubstitutedheteroaryl ring. In certain embodiments, R^(D5) and one R^(C) are joinedto form a substituted 7-membered heteroaryl ring. In certainembodiments, R^(D5) and one R^(C) are joined to form an unsubstituted7-membered heteroaryl ring. In certain embodiments, R^(D5) and one R^(C)are joined to form a substituted 5-membered heteroaryl ring. In certainembodiments, R^(D5) and one R^(C) are joined to form an unsubstituted5-membered heteroaryl ring.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, andprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

R^(D5) and one R^(C) may be joined to form a substituted heterocyclicring. R^(D5) and one R^(C), may also be joined to form an unsubstitutedheterocyclic ring. In certain embodiments, R^(D5) and one R^(C) arejoined to form a substituted 6-membered heterocyclic ring. In certainembodiments, R^(D5) and one R^(C) are joined to form an unsubstituted6-membered heterocyclic ring.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

R^(D5) and one R^(C) may be joined to form a substituted orunsubstituted 5-membered heterocyclic ring.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of formula:

-   -   (QL-XII-47),        or a pharmaceutically acceptable salt, solvate, hydrate,        polymorph, co-crystal, tautomer, stereoisomer, isotopically        labeled derivative, or prodrug thereof.

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising acompound of the present invention, e.g., a compound of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, as described herein, and optionally apharmaceutically acceptable excipient. In certain embodiments, thecompound of the present invention, or a pharmaceutically acceptable saltthereof, is provided in an effective amount in the pharmaceuticalcomposition. In certain embodiments, the effective amount is atherapeutically effective amount. In certain embodiments, the effectiveamount is a prophylactically effective amount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of the presentinvention (the “active ingredient”) into association with a carrier orexcipient, and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping, and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20),polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate(Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate(Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitanmonooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylenemonostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.Cremophor™), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether(Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor™,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active ingredient can be in micro-encapsulated form with one or moreexcipients as noted above. The solid dosage forms of tablets, dragees,capsules, pills, and granules can be prepared with coatings and shellssuch as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent invention contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers, or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) and as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition of the invention can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.1/1.0% (w/w) solution and/or suspension of the activeingredient in an aqueous or oily liquid carrier or excipient. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease being treated and theseverity of the disorder; the activity of the specific active ingredientemployed; the specific composition employed; the age, body weight,general health, sex, and diet of the subject; the time ofadministration, route of administration, and rate of excretion of thespecific active ingredient employed; the duration of the treatment;drugs used in combination or coincidental with the specific activeingredient employed; and like factors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. The desired dosage can be delivered three times a day, twotimes a day, once a day, every other day, every third day, every week,every two weeks, every three weeks, or every four weeks. In certainembodiments, the desired dosage can be delivered using multipleadministrations (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or more administrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds of the invention may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that the therapy employedmay achieve a desired effect for the same disorder, and/or it mayachieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. In will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.

Exemplary additional therapeutically active agents include, but are notlimited to, anti-cancer agents, anti-diabetic agents, anti-inflammatoryagents, immunosuppressant agents, and a pain-relieving agent.Therapeutically active agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The kits provided may comprise an inventive pharmaceutical compositionor compound and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of an inventive pharmaceutical composition or compound. Insome embodiments, the inventive pharmaceutical composition or compoundprovided in the first container and the second container are combined toform one unit dosage form.

Thus, in one aspect, provided are kits for preventing and/or treating aninfectious disease (e.g., a viral disease or viral infection) of asubject. In certain embodiments, the kits include a first containercomprising a compound, or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, prodrug, and composition thereof; and an instructionfor administering the compound, or a pharmaceutically acceptable salt,solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, prodrug, and composition thereof, to asubject to prevent or treat the infectious disease. The first containerof the provided kit may comprise a compound of the present invention. Incertain embodiments, the first container comprises QL-XII-47, or apharmaceutical salt thereof. In certain embodiments, the first containercomprises QL-XII-56, or a pharmaceutical salt thereof. In certainembodiments, the first container comprises a therapeutically effectiveamount of an inventive compound. In certain embodiments, the firstcontainer comprises a prophylactically effective amount of an inventivecompound.

The kits of the present invention may be used for treating or preventingDengue fever, Dengue hemorrhagic fever (DHF), Dengue shock syndrome(DSS), hepatitis B, hepatitis C, fulminant viral hepatitis, severe acuterespiratory syndrome (SARS), viral myocarditis, influenza A virusinfection, influenza B virus infection, parainfluenza virus infection,RS virus (RSV) infections (e.g., RSV bronchiolitis, RSV pneumonia,especially infant and childhood RSV infections and RSV pneumonia in thepatients with cardiopulmonary disorders), measles virus infection,vesicular stomatitis virus infection, rabies virus infection, Ebolavirus infection, Japanese encephalitis, Junin virus infection, humancytomegalovirus infection, herpes simplex virus 1 infection, poliovirusinfection, Marburg virus infection, Lassa fever virus infection,Venezuelan equine encephalitis, Rift Valley Fever virus infection,Korean hemorrhagic fever virus infection, Crimean-Congo hemorrhagicfever virus infection, HIV infection, encephalitis, Saint Louiseencephalitis, Kyasanur Forest disease, Murray Valley encephalitis,tick-borne encephalitis, West Nile encephalitis, yellow fever, and/orviral infections in subjects with immune disorders. In certainembodiments, the provided kits are used for treating or preventingDengue fever. In certain embodiments, the provided kits are used fortreating or preventing Dengue hemorrhagic fever (DHF). In certainembodiments, the provided kits are used for treating or preventingDengue shock syndrome (DSS). The kits of the present invention may alsobe used for treating or preventing a disease caused by Flaviviridaevirus (e.g., Dengue virus (DENV), including Dengue virus 1 (DENV1),Dengue virus 2 (DENV2), Dengue virus 3 (DENV3), and Dengue virus 4(DENV4); West Nile virus; tick-borne encephalitis virus; yellow fevervirus; hepatitis C virus; hepatitis G virus; bovine viral diarrhea;classical swine fever virus; and hog cholera virus), Kunjin virus,Japanese encephalitis virus, vesicular stomatitis virus (VSV), vesicularstomatitis virus (VSV) pseudotyped with rabies glycoprotein, vesicularstomatitis virus (VSV) pseudotyped with Ebola glycoprotein, herpessimplex virus 1 (HSV-1), human cytomegalovirus (HCMV), poliovirus, Juninvirus, Ebola virus, Marburg virus (MARV), Lassa fever virus (LASV),Venezuelan equine encephalitis virus (VEEV), Rift Valley Fever virus(RVFV), hepatitis B virus, cytomegalovirus, papillomavirus, coronavirus,Epstein-Barr virus (EBV), human immunodeficiency virus (HIV),orthomyxovirus, paramyxovirus, arenavirus, bunyavirus, adenovirus,poxvirus, retrovirus, rhabdovirus, picornavirus, or herpesvirus. Incertain embodiments, the provided kits are used for treating orpreventing a disease caused by Flaviviridae virus. In certainembodiments, the provided kits are used for treating or preventing adisease caused by Dengue virus (DENV). In certain embodiments, theprovided kits are used for treating or preventing a disease caused byDengue virus 1 (DENV1), Dengue virus 2 (DENV2), Dengue virus 3 (DENV3),or Dengue virus 4 (DENV4).

In certain embodiments, the subject administered the inventive compoundor composition is a mammal. In certain embodiments, the subject is ahuman. In certain embodiments, the subject is a domesticated animal,such as a dog, cat, cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a companion animal such as a dog or cat. Incertain embodiments, the subject is a livestock animal such as a cow,pig, horse, sheep, or goat. In certain embodiments, the subject is a zooanimal. In another embodiment, the subject is a research animal such asa rodent or non-human primate. In certain embodiments, the subject is anon-human transgenic animal such as a transgenic mouse or transgenicpig. In certain embodiments, the subject is a fish.

Methods of Treatment and Uses

In one aspect, the present invention provides methods for the preventionand/or treatment of infectious diseases in a subject suffered therefrom.In certain embodiments, the methods of prevention and/or treatmentinclude administering to a subject with an infectious disease aneffective amount of a compound of the present invention (e.g., QL-XII-47or QL-XII-56), or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeledderivative, prodrug, or pharmaceutical composition thereof. In certainembodiments, the methods of prevention and/or treatment compriseadministering to a subject with an infectious disease an effectiveamount of QL-XII-47, or a pharmaceutically acceptable salt thereof. Incertain embodiments, the methods of prevention and/or treatment compriseadministering to a subject with an infectious disease an effectiveamount of QL-XII-56, or a pharmaceutical salt thereof.

In certain embodiments, the effective amount is a therapeuticallyeffective amount. In certain embodiments, the effective amount is aprophylactically effective amount.

The infectious disease prevented and/or treated by the compounds orpharmaceutical compositions of the present invention is typically causedby a virus. In certain embodiments, the infectious disease is preventedand/or treated by blocking entry of the virus into a host cell. Entry ofa virus into a host cell involves an early entry step that occurs beforethe uptake of the virus by the host cell. Entry of a virus into a hostcell also involves a late entry step that occurs after the uptake of thevirus by the host cell but prior to the release of the genome of thevirus from the virus's nucleocapsid. In certain embodiments, entry ofthe virus is blocked at an early entry step. In certain embodiments,entry of the virus is blocked at a late entry step. In certainembodiments, the infectious disease is prevented and/or treated byreducing the count of the virus in the subject. In certain embodiments,the infectious disease is prevented and/or treated by inhibiting theactivity of the virus in the subject. In certain embodiments, theinfectious disease is prevented and/or treated by reducing thesusceptibility of a host factor in the subject to the virus. In certainembodiments, the infectious disease is prevented and/or treated byattaching a compound of the present invention to a cysteine residue ofthe host factor. In certain embodiments, the infectious disease isprevented and/or treated by irreversible binding of a compound of thepresent invention to a cysteine residue of the host factor. In certainembodiments, the infectious disease is prevented and/or treated bycovalently attaching a compound of the present invention to a cysteineresidue of the host factor.

In certain embodiments, the infectious disease prevented and/or treatedby the inventive compounds is caused by Flaviviridae virus. In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Dengue virus (DENV). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Dengue virus 1 (DENV1). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Dengue virus 2 (DENV2). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Dengue virus 3 (DENV3). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Dengue virus 4 (DENV4). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Kunjin virus. In certain embodiments,the infectious disease prevented and/or treated by the inventivecompounds is caused by Japanese encephalitis virus. In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by vesicular stomatitis virus (VSV). Incertain embodiments, the infectious disease prevented and/or treated bythe inventive compounds is caused by vesicular stomatitis virus (VSV)pseudotyped with rabies glycoprotein. In certain embodiments, theinfectious disease prevented and/or treated by the inventive compoundsis caused by vesicular stomatitis virus (VSV) pseudotyped with Ebolaglycoprotein. In certain embodiments, the infectious disease preventedand/or treated by the inventive compounds is caused by herpes simplexvirus 1 (HSV-1). In certain embodiments, the infectious diseaseprevented and/or treated by the inventive compounds is caused by humancytomegalovirus (HCMV). In certain embodiments, the infectious diseaseprevented and/or treated by the inventive compounds is caused bypoliovirus. In certain embodiments, the infectious disease preventedand/or treated by the inventive compounds is caused by Junin virus. Incertain embodiments, the infectious disease prevented and/or treated bythe inventive compounds is caused by Ebola virus. In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Marburg virus (MARV). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Lassa fever virus (LASV). In certainembodiments, the infectious disease prevented and/or treated by theinventive compounds is caused by Venezuelan equine encephalitis virus(VEEV). In certain embodiments, the infectious disease prevented and/ortreated by the inventive compounds is caused by Rift Valley Fever virus(RVFV). The infectious disease prevented and/or treated by the inventivecompounds may also be caused by, without limitation, West Nile virus,tick-borne encephalitis virus, yellow fever virus, hepatitis C virus,hepatitis G virus, bovine viral diarrhea, classical swine fever virus,hog cholera virus, hepatitis B virus, cytomegaloviruses,papillomaviruses, coronaviruses, Epstein-Barr virus (EBV), humanimmunodeficiency virus (HIV), orthomyxoviruses, paramyxoviruses,arenaviruses, bunyaviruses, adenoviruses, poxviruses, retroviruses,rhabdoviruses, picornaviruses, or herpesviruses.

In certain embodiments, the infectious disease prevented and/or treatedby the inventive compounds is Dengue fever. In certain embodiments, theinfectious disease prevented and/or treated by the inventive compoundsis Dengue hemorrhagic fever (DHF). In certain embodiments, theinfectious disease prevented and/or treated by the inventive compoundsis Dengue shock syndrome (DSS). Other infectious disease that may beprevented and/or treated by the inventive compounds include, but notlimited to, hepatitis B, hepatitis C, fulminant viral hepatitis, severeacute respiratory syndrome (SARS), viral myocarditis, influenza A virusinfection, influenza B virus infection, parainfluenza virus infection,RS virus (RSV) infections (e.g., RSV bronchiolitis, RSV pneumonia,especially infant and childhood RSV infections and RSV pneumonia in thepatients with cardiopulmonary disorders), measles virus infection,vesicular stomatitis virus infection, rabies virus infection, Ebolavirus infection, Japanese encephalitis, Junin virus infection, humancytomegalovirus infection, herpes simplex virus 1 infection, poliovirusinfection, Marburg virus infection, Lassa fever virus infection,Venezuelan equine encephalitis, Rift Valley Fever virus infection,Korean hemorrhagic fever virus infection, Crimean-Congo hemorrhagicfever virus infection, HIV infection, encephalitis, Saint Louiseencephalitis, Kyasanur Forest disease, Murray Valley encephalitis,tick-borne encephalitis, West Nile encephalitis, yellow fever, and viralinfections in subjects with immune disorders.

The present invention also provides methods of reducing viral load in asubject. The methods of reducing viral load include administering to thesubject an effective amount of a compound of the present invention(e.g., QL-XII-47 or QL-XII-56), or a pharmaceutically acceptable salt,solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, prodrug, or pharmaceutical compositionthereof. The inventive compounds may be administered within 1 day, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, or 1month of exposure to the virus. In certain embodiments, the time ofviral clearance is reduced. In certain embodiments, morbidity ormortality of the subject, who may or may not have been infected with thevirus or has been exposed to the virus, is reduced.

Viral load may be determined by measuring the titer or level of virus ina tissue or bodily fluid of the subject. Measuring the viral load can beaccomplished by any conventional assay, such as ones described in theliterature (see, e.g., Medical Microbiology; 3rd Ed.; Murray et al.,eds.; Mosby, Inc.: Philadelphia, Pa., 1998). In certain embodiments,viral load is reduced to a undetectable level. In certain embodiments,viral load is reduced to a low level of, for example, less than about20,000 cpm (genome copies per milliliter of serum of the subject), lessthan about 5000 cpm, less than about 2000 cpm, less than about 500 cpm,or less than about 200 cpm. In certain embodiments, viral load isreduced by at least about 5%, at least about 10%, at least about 25%, atleast about 50%, at least about 75%, at least about 90%, at least about95%, or at least about 99%. In certain embodiments, the inventivemethods achieve a sustained viral response, e.g., the viral load isreduced to an undetectable or low level for a period of at least aboutone month, at least about two months, at least about three months, atleast about four months, at least about five months, at least about sixmonths, at least about one year, at least about two years, at leastabout three years, at least about four years, or at least about fiveyears following cessation of administering a compound of the presentinvention to the subject.

The present invention also involves methods of preventing a viralinfection in a subject who was or may be exposed to a virus. The methodsof preventing a viral infection include administering to the subject whowas or may be exposed to a virus an effective amount of a compound ofthe present invention (e.g., QL-XII-47 or QL-XII-56), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative,prodrug, or pharmaceutical composition thereof.

In certain embodiments, the subject was exposed to a virus. In certainembodiments, the subject may be exposed to a virus. In certainembodiments, the viral infection is prevented by blocking entry of thevirus into the cells of the subject.

In certain embodiments, the virus to which a subject was or may beexposed is Flaviviridae virus. In certain embodiments, the virus towhich a subject was or may be exposed is Dengue virus (DENV). In certainembodiments, the virus to which a subject was or may be exposed isDengue virus 1 (DENV1). In certain embodiments, the virus to which asubject was or may be exposed is Dengue virus 2 (DENV2). In certainembodiments, the virus to which a subject was or may be exposed isDengue virus 3 (DENV3). In certain embodiments, the virus to which asubject was or may be exposed is Dengue virus 4 (DENV4). In certainembodiments, the virus to which a subject was or may be exposed isKunjin virus. In certain embodiments, the virus to which a subject wasor may be exposed is Japanese encephalitis virus. In certainembodiments, the virus to which a subject was or may be exposed isvesicular stomatitis virus (VSV). In certain embodiments, the virus towhich a subject was or may be exposed is vesicular stomatitis virus(VSV) pseudotyped with rabies glycoprotein. In certain embodiments, thevirus to which a subject was or may be exposed is vesicular stomatitisvirus (VSV) pseudotyped with Ebola glycoprotein. In certain embodiments,the virus to which a subject was or may be exposed is herpes simplexvirus 1 (HSV-1). In certain embodiments, the virus to which a subjectwas or may be exposed is human cytomegalovirus (HCMV). In certainembodiments, the virus to which a subject was or may be exposed ispoliovirus. In certain embodiments, the virus to which a subject was ormay be exposed is Junin virus. In certain embodiments, the virus towhich a subject was or may be exposed is Ebola virus. In certainembodiments, the virus to which a subject was or may be exposed isMarburg virus (MARV). In certain embodiments, the virus to which asubject was or may be exposed is Lassa fever virus (LASV). In certainembodiments, the virus to which a subject was or may be exposed isVenezuelan equine encephalitis virus (VEEV). In certain embodiments, thevirus to which a subject was or may be exposed is Rift Valley Fevervirus (RVFV). The virus to which a subject was or may be exposed mayalso include, but not limited to, West Nile virus, tick-borneencephalitis virus, yellow fever virus, hepatitis C virus, hepatitis Gvirus, bovine viral diarrhea, classical swine fever virus, hog choleravirus, hepatitis B virus, cytomegaloviruses, papillomaviruses,coronaviruses, Epstein-Barr virus (EBV), human immunodeficiency virus(HIV), orthomyxoviruses, paramyxoviruses, arenaviruses, bunyaviruses,adenoviruses, poxviruses, retroviruses, rhabdoviruses, picornaviruses,and herpesviruses.

Another aspect of the present invention relates to methods of inhibitingviral replication in vitro, in vivo, and/or ex vitro.

Another aspect of the present invention relates to methods of inhibitingviral production in vitro, in vivo, and/or ex vitro.

Another aspect of the present invention relates to methods of inhibitingviral activity in vitro, in vivo, and/or ex vitro.

Another aspect of the present invention relates to methods of killing avirus in vitro, in vivo, and/or ex vitro.

In certain embodiments, the methods of inhibiting viral replication,viral production, inhibiting viral activity, or killing a virus includecontacting a virus in vitro, in vivo, and/or ex vitro with an effectiveamount of a compound of the present invention (e.g., QL-XII-47 orQL-XII-56), or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeledderivative, prodrug, or pharmaceutical composition thereof.

Another aspect of the invention relates to methods of screening alibrary of compounds to identify one or more compounds that are usefulin the treatment and/or prevention of a viral infection in a subjectsuffering therefrom, in inhibiting viral replication in vitro, in vivo,and/or ex vitro, in inhibiting viral production in vitro, in vivo,and/or ex vitro, in inhibiting viral activity in vitro, in vivo, and/orex vitro, and/or in killing a virus in vitro, in vivo, and/or ex vitro.In certain embodiments, the library of compounds is a library ofcompounds of the present invention. The methods of screening a libraryinclude providing at least two different compounds of the presentinvention, or pharmaceutically acceptable salts, solvates, hydrates,polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeledderivatives, or prodrugs thereof, or pharmaceutical compositionsthereof; and performing at least one assay using the different compoundsof the present invention, or pharmaceutically acceptable salts,solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers,isotopically labeled derivatives, or prodrugs thereof, or pharmaceuticalcompositions thereof, to detect one or more characteristics. In certainembodiments, the methods of screening a library include providing atleast two different compounds of the present invention, orpharmaceutically acceptable salts thereof, or pharmaceuticalcompositions thereof; and performing at least one assay using thedifferent compounds of the present invention, or pharmaceuticallyacceptable salts thereof, or pharmaceutical compositions thereof, todetect one or more characteristics. In certain embodiments, thecharacteristic is a characteristic associated with the viral infection,the rival replication, and/or the viral activity. In certainembodiments, the characteristic is a desired characteristic. In certainembodiments, the desired characteristic is usefulness in treating and/orpreventing the viral infection in the subject. In certain embodiments,the desired characteristic is usefulness in reducing the viral load inthe subject. In certain embodiments, the desired characteristic isusefulness in inhibiting the viral replication. In certain embodiments,the desired characteristic is usefulness in inhibiting the viralproduction. In certain embodiments, the desired characteristic isusefulness in inhibiting the viral activity. In certain embodiments, thedesired characteristic is usefulness in blocking entry of the virus intoa host cell. In certain embodiments, the desired characteristic isusefulness in kill the virus. In certain embodiments, the desiredcharacteristic is usefulness in preventing or inhibiting entry of avirus into a host cell. The characteristic to be detected may also be anundesired characteristic associated with the viral infection, the rivalreplication, and/or viral activity. In certain embodiments, theundesired characteristic is increased viral load in a host cell. Incertain embodiments, the undesired characteristic is increased viralreplication. In certain embodiments, the undesired characteristic isincreased viral production. In certain embodiments, the undesiredcharacteristic is increased viral activity. The present invention alsoprovides methods of screening a library of compounds to identify one ormore compounds that prevent or inhibit entry of a virus into a hostcell. In certain embodiments, the methods of screening include providingat least two different compounds of the present invention, orpharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,or prodrugs thereof, and performing at least one assay using thecompounds of the present invention, or pharmaceutically acceptablesalts, solvates, hydrates, polymorphs, co-crystals, tautomers,stereoisomers, isotopically labeled derivatives, or prodrugs thereof, todetect entry of a virus into a host cell.

The different compounds of the present invention may be provided fromnatural sources (see, e.g., Sternberg et al., Proc. Nat. Acad. Sci. USA,(1995) 92:1609-1613) or generated by synthetic methods such ascombinatorial chemistry (see, e.g., Ecker et al., Bio/Technology, (1995)13:351-360 and U.S. Pat. No. 5,571,902). In certain embodiments, thedifferent compounds are provided by liquid-phase or solution synthesis.In certain embodiments, the different compounds are provided bysolid-phase synthesis. In certain embodiments, the different compoundsare provided by a high-throughput, parallel, or combinatorial synthesis.In certain embodiments, the different compounds are provided by alow-throughput synthesis. In certain embodiments, the differentcompounds are provided by a one-pot synthesis. The different compoundsmay be provided robotically or manually. In certain embodiments, thestep of providing at least two different compounds of the presentinvention include arraying into at least two vessels at least twodifferent compounds of the present invention wherein the compounds arebound to solid supports, cleaving the compounds from the solid supports,and dissolving the cleaved compounds in a solvent. The solid supportsinclude, but do not limit to, beads (e.g., resin beads and magneticbeads), hollow fibers, solid fibers, plates, dishes, flasks, meshes,screens, and membranes. In certain embodiments, the solid supports arebeads. In certain embodiments, one solid support is capable ofsupporting at least 50 nmol of a compound. In certain embodiments, onesolid support is capable of supporting at least 100 nmol of a compound.In certain embodiments, one solid support is capable of supporting atleast 200 nmol of a compound. Each vessel may contain one or moresupport-bound compounds of the present invention. In certainembodiments, each vessel contains one support-bound compounds of thepresent invention. The solid supports and/or the compounds may belabeled with one or more labeling agents for the identification ordetection of the compounds. The vessels may be wells of a microtiterplate. The solvent may be an inorganic solvent, organic solvent, or amixture thereof. The steps of arraying, cleaving, and dissolving may beperformed robotically or manually.

Typically, the methods of screening a compound library involve at leastone assay. In certain embodiments, the assay is performed to detectentry of a virus into a host cell of a subject. In certain embodiments,the assay is performed to determine the extent of the interactionbetween a compound of the present invention and a host factor of thesubject using methods known in the art (see, e.g., Chu et al., J. Am.Chem. Soc. (1996) 118:7827-7835). In certain embodiments, the assay isan immunoassay, such as a sandwich-type assay, competitive bindingassay, one-step direct test, two-step test, or blot assay. The step ofperforming at least one assay may be performed robotically or manually.In certain embodiments, an early viral entry step is prevented orinhibited. In certain embodiments, a late viral entry step is preventedor inhibited. The virus whose entry into the host cell may be preventedor inhibited include, but do not limit to, Flaviviridae viruses (e.g.,Dengue virus (DENV), including Dengue virus 1 (DENV1), Dengue virus 2(DENV2), Dengue virus 3 (DENV3), and Dengue virus 4 (DENV4); West Nilevirus; tick-borne encephalitis virus; yellow fever virus; hepatitis Cvirus; hepatitis G virus; bovine viral diarrhea; classical swine fevervirus; and hog cholera virus), Kunjin virus, Japanese encephalitisvirus, vesicular stomatitis virus (VSV), vesicular stomatitis virus(VSV) pseudotyped with rabies glycoprotein, vesicular stomatitis virus(VSV) pseudotyped with Ebola glycoprotein, herpes simplex virus 1(HSV-1), human cytomegalovirus (HCMV), poliovirus, Junin virus, Ebolavirus, Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equineencephalitis virus (VEEV), Rift Valley Fever virus (RVFV), hepatitis Bvirus, cytomegaloviruses, papillomaviruses, coronaviruses, Epstein-Barrvirus (EBV), human immunodeficiency virus (HIV), orthomyxoviruses,paramyxoviruses, arenaviruses, bunyaviruses, adenoviruses, poxviruses,retroviruses, rhabdoviruses, picornaviruses, and herpesviruses. Incertain embodiments, the virus whose entry into the host cell may beprevented or inhibited is Flaviviridae virus. In certain embodiments,the virus whose entry into the host cell may be prevented or inhibitedis Dengue virus (DENV). In certain embodiments, the virus whose entryinto the host cell may be prevented or inhibited is Dengue virus 1(DENV1), Dengue virus 2 (DENV2), Dengue virus 3 (DENV3), or Dengue virus4 (DENV4).

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and inventivecompounds provided herein and are not to be construed in any way aslimiting their scope.

Example 1. Synthesis of the Compounds

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.Various intermediates useful for preparation of the compounds of theinvention can be prepared in accordance with methods described in theart (Upasani et al., J. Med. Chem. (1997) 40:73-84; and Hogenkamp etal., J. Med. Chem. (1997) 40:61-72) and using the appropriate reagents,starting materials, and purification methods known to those skilled inthe art. Representative methods are demonstrated in Schemes 1-4. Thecompounds of the invention can be prepared using the intermediatesdescribed above. For example, a general method for preparing QL-XII-47is illustrated in Scheme 1.

Compounds 1 (480 mg, 2 mmol, 1 equiv.) and 2 (470 mg, 2 mmol, 1 equiv.)were combined in 1,4-dioxane (13 mL) and heated at 100° C. for 4 h,cooled to room temperature, poured into brine, and extracted with ethylacetate (3×). The organic phase was dried over sodium sulfate, filtered,and concentrated. The resulting residue was purified by flashchromatography on SiO₂ (methanol:dichloromethane; 1:15 to 1:9) toprovide compound 3 (560 mg, 64% yield, LC-MS m/z (M+H)=441.15).

Compound 3 (440 mg, 1 mmol, 1 equiv.) was dissolved in ethyl acetate (7mL) and treated with SnCl₂ (950 mg, 5 mmol, 5 equiv.). The resultingmixture was heated at 65° C. for 4 h and then filtered throughCelite^(©). The filtrate was dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by flash chromatographyon SiO₂ (methanol:dichloromethane; 1:10) to afford compound 4 (310 mg,70% yield, LC-MS m/z (M+H)=411.23).

Compound 4 (300 mg, 0.73 mmol, 1 equiv.) was dissolved indichloromethane (5 mL) and treated with carbonyl diimidazole (140 mg,0.88 mmol, 1.2 equiv.) at room temperature. After 4 h, the reactionmixture was quenched with brine and extracted with dichloromethane (3×),and the combined organic layers were dried over sodium sulfate.Following filtration and concentration of the organic solution, theresulting crude residue was dissolved in THF (5 mL) and treated with NaH(53 mg, 2.2 mmol, 3 equiv.) and MeI (55 μL, 0.88 mmol, 1.2 equiv.).After stirring at room temperature for 12 h, the reaction was quenchedwith NH₄Cl (saturated) and extracted with dichloromethane (3×). Theorganic solution was then dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by flash chromatographyon SiO₂ (methanol:dichloromethane; 1:10) to afford compound 5 (147 mg,45% yield, LC-MS m/z (M+H)=451.93).

Compounds 5 (135 mg, 0.3 mmol, 1 equiv.) and 6 (57 mg, 0.45 mmol, 1.5equiv.) were dissolved in 1,4-dioxane (2 mL) and treated with NaHCO₃(1.3 mL, 1 N, 3 equiv.) and PdCl₂(Ph₃P)₂ (21 mg, 0.03 mmol, 0.1 equiv.).The resulting solution was heated at 100° C. for 3 h, cooled to roomtemperature, and extracted with dichloromethane (3×). The organicsolution was then dried over sodium sulfate, filtered, and concentrated.The resulting residue was purified by flash chromatography on SiO₂(methanol:dichloromethane; 1:10) to afford compound 7 (67 mg, 45% yield.LC-MS m/z (M+H)=497.24).

Compound 7 (50 mg, 0.1 mmol, 1 equiv.) was dissolved in 1,4-dioxane (3mL), treated with HCl in 1,4-dioxane (0.2 mL of a 4 N solution, 8equiv.), stirred at room temperature for 1 h, and then treated withtriethylamine (140 μL, 1 mmol, 10 equiv.) and acryloyl chloride (8 μL,0.105 mmol, 1.05 equiv.). The resulting solution was stirred for 30 min,quenched with sodium bicarbonate (saturated), and extracted withdichloromethane (3×). The organic solution was then dried over sodiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on SiO₂ (methanol:dichloromethane; 1:30 to 1:10) toprovide compound 8 (13 mg, 30% yield, LC-MS m/z (M+H)=451.23).

Compounds 9 (1.35 g, 5 mmol, 1 equiv.) and 10 (760 mg, 5 mmol, 1 equiv.)were dissolved in 1,4-dioxane (10 mL) and heated at 100° C. for 4 h. Thereaction mixture was then cooled to room temperature, washed with sodiumbicarbonate (saturated) and extracted with ethyl acetate (3×). Theorganic solution was dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by flash chromatographyon SiO₂ (methanol:dichloromethane; 1:10) to afford compound 11 (1.46 g,76% yield, LC-MS m/z (M+H)=386.13).

Compound 11 (1.4 g, 3.6 mmol, 1 equiv.) was dissolved in ethanol (20 mL)at room temperature and treated with NaBH₄ (680 mg, 18 mmol, 5 equiv.)in 5 portions. The resulting solution was stirred for 4 h and filteredthrough celite. The filtrate was then washed with NaHCO₃ (saturated) andextracted with ethyl acetate (3×). The organic solution was dried oversodium sulfate, filtered, and concentrated. The resulting residue waspurified by flash chromatography on SiO₂ (methanol:dichloromethane;1:10) to afford compound 12 (620 mg, 50% yield, LC-MS m/z (M+H)=344.14).

Compound 12 (620 mg, 1.8 mmol, 1 equiv.) was dissolved indichloromethane (20 mL) and treated with MnO₂ (3.1 g, 5 equiv. weights).After 4 hours, the reaction mixture was filtered through Celite^(©), andthe filtrate was concentrated. The residue was then dissolved in EtOH(20 mL) in a sealed tube, treated with K₂CO₃ (745 mg, 5.4 mmol, 3equiv.) followed by triethylphophonoacetate (1 mL, 5.4 mmol, 3 equiv.),and heated to 100° C. for 12 h. The reaction mixture was cooled to roomtemperature and filtered through Celite©, and the filtrate was extractedwith ethyl acetate (3×). The organic phase was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by flash chromatography on SiO₂(methanol:dichloromethane; 1:20) to provide compound 13 (280 mg, 43%yield, LC-MS m/z (M+H)=366.13).

Compound 13 (250 mg, 0.68 mmol, 1 equiv.) was dissolved in ethyl acetate(10 mL) at room temperature, treated with SnCl₂.2H₂O (765 mg, 3.4 mmol,5 equiv.) and heated at 65° C. for 4 h. The reaction mixture was cooledand filtered through Celite^(©). The filtrate was washed with NaHCO₃ andbrine, dried over sodium sulfate, filtered, and concentrated. Theresulting crude residue was dissolved in dichloromethane (10 mL) andtreated with Et₃N (190 μL, 1.36 mmol, 2 equiv.) and acryloyl chloride(27 μL, 0.34 mmol, 0.5 equiv.). The reaction mixture was stirred at roomtemperature for 30 min, quenched with NaHCO₃ (saturated) and extractedwith dichloromethane (3×). The organic phase was washed with water andbrine, dried over sodium sulfate, filtered, and concentrated. Theresulting residue was purified by flash chromatography on SiO₂(methanol:dichloromethane; 1:30 to 1:10) to afford compound 14 (78 mg,30% yield, LC-MS m/z (M+H)=390.11).

Compound 14 (78 mg, 0.2 mmol, 1 equiv.) was dissolved in 1,4-dioxane (5mL) and treated with compound 15 (26 mg, 0.24 mmol, 1.2 equiv.), NaHCO₃(0.6 mL, 1 N in water, 3 equiv.) and PdCl₂(Ph₃P)₂ (14 mg, 0.02 mmol, 0.1equiv.). The reaction mixture was heated at 100° C. for 3 h, cooled toroom temperature, filtered through Celite^(©), and the filtrate wasextracted with ethyl acetate (3×). The organic phase was then washedwith water and brine, dried over sodium sulfate, filtered, andconcentrated. The resulting residue was purified by flash chromatographyon SiO₂ (methanol:dichloromethane; 1:30 to 1:10) to afford compound 16(40 mg, 48% yield, LC-MS m/z (M+H)=422.20).

Compound 13 (360 mg, 1 mmol, 1 equiv.) was dissolved in 1,4-dioxane (5mL) at room temperature and treated with compound 6 (190 mg, 1.5 mmol,1.5 equiv.), PdCl₂(Ph₃P)₂ (70 mg, 0.1 mmol, 0.1 equiv.) and NaHCO₃ (3mL, 1 N in water, 3 equiv.). The reaction mixture was heated at 100° C.for 3 h, cooled to room temperature, filtered through celite, and thefiltrate was extracted with ethyl acetate (3×). The organic phase wasthen washed with water and brine, dried over sodium sulfate, filteredand concentrated. The resulting residue was purified by flashchromatography on SiO₂ (methanol:dichloromethane; 1:30 to 1:10) toafford compound 17 (210 mg, 52% yield, LC-MS m/z (M+H)=412.14).

Compound 17 (200 mg, 0.48 mmol, 1 equiv.) was dissolved in ethyl acetate(10 mL) at room temperature, treated with SnCl₂.2H₂O (540 mg, 2.4 mmol,5 equiv.) and heated at 65° C. for 4 h. Following, the reaction mixturewas cooled and filtered through celite. The resulting filtrate waswashed with NaHCO₃ and brine, dried over sodium sulfate, filtered, andconcentrated. The residue was then purified by flash chromatography onSiO₂ (methanol:dichloromethane; 1:30 to 1:10) to afford compound 18 (95mg, 52% yield, LC-MS m/z (M+H)=382.24).

4-Bromo-but-2-enoic acid (21 mg, 0.13 mmol, 1.3 equiv.) was dissolved indichloromethane (1 mL) and treated with (COCl)₂ (22 μL, 0.26 mmol, 2equiv.) and DMF (1 drop, 0.1 equiv.). After 1 h at room temperature, thesolvents were evaporated. The crude residue was then dissolved indichloromethane (1 mL) and treated with Et₃N (36 μL, 0.26 mmol, 2equiv.), and compound 18 (38 mg, 0.1 mmol, 1 equiv.). After 2 h, thesolvent was removed and the crude residue was dissolved in THF (1 mL)and treated with dimethylamine (0.13 mL in THF of 2 M solution, 0.26mmol, 2 equiv.). The reaction mixture was stirred for 2 h, quenched withNaHCO₃ (saturated), and extracted with dichloromethane (3×). The organicphase was washed with water and brine, dried over sodium sulfate,filtered, and concentrated. The resulting residue was purified by flashchromatography on SiO₂ (methanol:dichloromethane; 1:30 to 1:10) toafford compound 19 (12 mg, 25% yield, LC-MS m/z (M+H)=493.34).

It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by those skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in Greene et al., Protecting Groups inOrganic Synthesis, 2^(nd) Ed.; Wiley: New York, 1991, and referencescited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include, but are not limited to,trituration, recrystallization, column chromatography, or HPLC.

Example 2. X-Ray Crystal Structure of QL-X-138

QL-X-138 (see FIG. 7 for the chemical structure), a structural analog ofQL-XII-47, has been successfully crystallized with EGFR kinase thatcontains a cysteine in the same position as the Tec-family kinases (FIG.7). The structure shows the expected hydrogen bond between the quinolinenitrogen and the “hinge” region amino acid Met793. The pyrazole group isdirected towards a hydrophobic pocket at the back of the ATP-pocketwhich the para-methyl aniline group is nestled beneath the P loop and acovalent bond with Cys797 is apparent.

Example 3. Cell-Based Mini-Screen of Acrylamide-Containing Compounds forthe Identification of Novel Covalent Inhibitors of DENV Methods

Small molecule screens (Chu et al., Proc. Nat. Acad. Sci. USA (2007)104:3520-3525) and RNAi (Sessions et al., Nature (2009) 458:1047-1050)have been utilized to identify host factors that are required for Denguevirus (DENV) replication, with a particular interest in host kinasesthat modulate DENV replication. As an extension of this work, acell-based mini-screen of a 30-compound subset of acrylamide-containingcompounds was performed to identify novel covalent inhibitors of DENV.The compounds were designed to react covalently upon binding in theproper orientation near a reactive cysteine.

Huh7 cells were seeded in 24-well plates and infected at an MOI(multiplicity of infection) of 1 with 100 μl of DENV2 New Guinea C(DENV2-NGC). Plates were incubated for 1 hour at 37° C. and rocked every15 min. Unadsorbed virus was removed by a PBS wash, after which 500 μlof Dulbecco's modified Eagle's medium (DMEM) supplemented with 2% FBSand the indicated concentrations of small molecule was added to eachwell. After incubation at 37° C. for 24 hours, the supernatants werecollected for DENV2 titration using a focus forming assay, described asfollows. BHK-21 cells were seeded in 24-well plates. Aliquots frominfections were thawed at 37° C. in a water bath. Ten-fold dilutions inEBSS were prepared in duplicate, and 100 μl of each dilution were addedto the cells. Plates were incubated for 1 hour at 37° C. and rockedevery 15 min. Unadsorbed virus was removed by washes with PBS, afterwhich 1 ml of MEM-α supplemented with carboxymethylcellulose (CMC),HEPES, and 2% FBS, was added to each well and incubated at 37° C. for 3days. The CMC overlay was aspirated, and cells were washed with PBS andfixed with methanol for 15 min at −20° C. After fixation, the cells werewashed with PBS and incubated for 1 hour at room temperature withanti-DENV2 C antibody (provided by John Aaskov), followed by incubationwith HRP-conjugated anti-mouse IgG antibody. The plates were revealedwith Vector VIP Peroxidase Substrate kit (Vector Laboratories SK-4600)following manufacturer's instructions. The results are shown in FIGS.2B, 2C, and 2G.

Huh7 cells were seeded in 96-well plates and infected at an MOI of 1with 100 μl of DENV2 supplemented with the indicated concentrations ofsmall molecule. As a positive control for cytotoxicity, some wells weresupplemented with 0.1% saponin. The plates were incubated for 24 hoursat 37° C., and the cell cytotoxicity was measured following theinstructions of the CellTiter-Glo Luminescent cell viability assay(Promega G7570). The results are shown in FIG. 2D.

Huh7 cells were infected at an MOI of 1 with DENV1-WP74, DENV2-NGC,DENV3-THD3, or DENV4-TVP360 as described in FIG. 2B. The supernatantscollected at 24 hours post-infection were analyzed by focus formingassay in Vero cells. The experimental set up for focus forming assay inVero cells was similar to what was described in FIG. 2B for BHK21 cells,except that the cells were incubated in DMEM for 4 days at 37° C. andrevealed using anti-DENV E antibody (4G2). The results are shown in FIG.2E.

Huh7 cells were infected at an MOI of 1 with Kunjin virus as describedin FIG. 2B. The supernatants collected at 24 hours post-infection wereanalyzed by plaque assay in BHK21 cells. The experimental set up forplaque assay was similar to what was described in FIG. 2B for focusforming assay, except that after 3 days incubation at 37° C., the cellswere stained with crystal violet to reveal the plaques. The results areshown in FIG. 2F.

Results

This screen allowed the identification of QL-XII-47, a tricyclicquinoline derivative, that causes >3-log₁₀ unit decrease in DENV2 NewGuinea C (DENV2-NGC) yield at single-digit micromolar concentrations(EC₉₀ 400 nM) (FIGS. 2A and 2B). It was confirmed that QL-XII-47 ismostly likely functioning as a covalent inhibitor by demonstrating thatQL-XII-47R, in which the reactive acrylamide has been replaced with anunreactive propyl amide, results in a complete loss of activity (FIGS.2A and 2C). No cytotoxicity was observed for QL-XII-47 at 20 μM, thehighest concentration tested (FIG. 2D). QL-XII-47 also inhibitsadditional DENV strains representative of the four DENV serotypes (DENV1to DENV4) and Kunjin virus, another flavivirus, in yield reductionassays (FIGS. 2E and 2F). In addition, QL-XI-76 was identified, in whichthe pyrazole of QL-XII-47 is replaced with a furan, as a negativecontrol compound that is devoid of anti-DENV activity at concentrationsup to 10 μM (FIGS. 2A and 2G). QL-XI-76 demonstrates that non-covalentinteractions are also key to QL-XII-47's activity and that the presenceof an electrophilic acrylamide moiety is not sufficient to conferanti-DENV activity.

Example 4. Time-of-Addition Experiments for the Investigation of theStage(s) of the Viral Life Cycle Affected by QL-XII-47 Methods

In order to investigate the stage(s) of the viral life cycle affected byQL-XII-47, time-of-addition experiments were performed.

The results shown in FIGS. 3A and 3B were obtained by using experimentsperformed essentially as described in Example 3. The small molecule wasdiluted in media and added to the cells at the indicated times pre- orpost-DENV2 infection.

The plasmids used for recombinant viral particles (RVP) production wereprovided by Ted Pierson (Ansarah-Sobrinho et al., Virology (2008)381:67-74). To produce RVPs, HEK293T cells were co-transfected withpCDNA6.2-D2.CprME (Ansarah-Sobrinho et al., Virology (2008) 381:67-74)and pWIIrep-REN-IB (Pierson et al., Virology (2006) 346:53-65) usingLipofectamine 2000 (Life Technologies 11668-019) according to themanufacturer's instructions. The supernatants were collected at 2 dayspost-transfection and filtered through a 0.45 μm filter to removecontaminant cells in the supernatants. Huh7 cells seeded in 48-wellplates were infected with 100 μl of RVPs. The plates were incubated for1 hour at 37° C. and rocked every 15 min. Unadsorbed RVPs were removedby a PBS wash, after which 300 μl of DMEM supplemented with 2% FBS andthe indicated concentrations of small molecule was added to each well.After incubation at 37° C. for 24 hours, the cells were collected andthe samples were processed following the instructions in the Renillaluciferase assay system (Promega E2810). The Renilla luciferase signalwas read using Perkin Elmer EnVision plate reader. The results are shownin FIG. 3C.

The plasmid containing a DENV2 replicon that expresses a reporterfirefly luciferase in place of DENV2 structural proteins was provided byEva Harris (Holden et al., Virology (2006) 344:439-452). In vitrotranscripts were synthesized from PstI linearized pDENrep-FH usingT7-Scribe Standard RNA IVT kit (CellScript C-AS3107) and m7G(5′)ppp(5′)ARNA cap structure analog (New England Biolabs S 1405L) following themanufacturers instructions. Huh7 cells were washed twice in PBS and1.10⁶ cells were electroporated with DENV2 replicon in vitro transcriptsusing ECM 830 electroporator (BTX Harvard Apparatus) at the followingsettings: 5 pulses at 820 V, 100 s per pulse with 1.1 s intervals. Afterelectroporation, the cells were seeded in 24-well plates and at 24 hourspost-electroporation, and the media was changed and supplemented withDMSO or 2 μM of the indicated small molecules. At 72 hourspost-electroporation, the cells were collected, and the samples wereprocessed following the instructions in the luciferase assay system(Promega E1483). The firefly luciferase signal was read using PerkinElmer EnVision plate reader. The results are shown in FIG. 3D.

The plasmid used for virus-like particles (VLP) production was providedby Stephen Harrison. Briefly, the codon optimized sequence ofDENV2-FGA/02 prM-E (Wang et al., PLoS ONE (2009) 4:e8325) was introducedin the pCDNA3.1 vector. To produce VLPs, Huh7 cells were transfectedwith pCDNA3.1-D2.VLP using Lipofectamine 2000 (Life Technologies11668-019) according to the manufacturer's instructions. At 4 hours posttransfection, the cells were treated with DMSO, 3 μM of QL-XII-47, or 10μM of Ki20227 or GNF2. The supernatants were collected at 24 hourspost-treatment and precipitated for 3 hours at 4° C. by the addition of0.075% of PEG 8000. The VLPs were pelleted by centrifugation at 10,000 gfor 15 min at 4° C. The pellet was suspended in 200 μl of 1×TNE (10 mMTris-HCl pH 7.5, 2.5 mM EDTA, 50 mM NaCl), loaded over a sucrose cushion(800 μl of 12.5% sucrose in 1×TNE), and centrifuged at 100,000 g for 2 hat 4° C. The supernatants were discarded, and the purified VLPs weresuspended in 50 μl of 1×TNE. 25 μl of purified VLPs were analyzed forDENV2 E protein expression by Western blotting using 4G2 antibody. Anequal amount of purified VLPs was loaded on a SDS-PAGE and submitted toCoomassie staining to control for equal loading of the VLPs-enrichedsupernatants. Steady state expression of DENV2 E protein in the celllysates was analyzed by Western blotting using 4G2 antibody. The resultsare shown in FIG. 3E.

Results

It was discovered that potent inhibition of DENV is still observed whencells are pretreated with QL-XII-47 for 6 hours and then washed prior toinfection with DENV (FIG. 3A). This strongly suggests that QL-XII-47acts via a host target and interferes with a step early in the DENV lifecycle. The time-of-addition experiments show that the maximal anti-DENVeffect was observed when QL-XII-47 is present at 0-3 hourspost-infection (FIG. 3B); QL-XII-47's inhibitory activity is lost overtime when QL-XII-47 is added at later times post-infection. Consistentwith the idea that QL-XII-47 inhibits steps early in the DENV life cycle(e.g., entry), it was found that QL-XII-47 has potent inhibitoryactivity in a single cycle reporter Dengue virus assay (RVP)(Ansarah-Sobrinho et al., Virology (2008) 381:67-74) that expresses aluciferase reporter upon successful entry and translation of asubgenomic replicon RNA (FIG. 3C) but does not have activity in an assayin which a subgenomic reporter replicon RNA is electroporated into cellsto bypass viral entry (FIG. 3D). Likewise, QL-XII-47 did not inhibit theyield of virus-like particles (VLPs) produced when a plasmid encodingthe prM-E proteins was transfected into cells (FIG. 3E), suggesting thatQL-XII-47 does not inhibit viral particle assembly or egress.

Example 5. Time-Course Experiments for the Determination of QL-XII-47'sEffect on the Different Stages of DENV Entry Methods

To better understand QL-XII-47's effect on DENV entry, a time courseexperiment was performed, and qRT-PCR and fluorescence in situhybridization were used to monitor the fate of the genomic RNA of theDENV inoculum in the presence and absence of QL-XII-47 (FIGS. 4A and4B).

Huh7 cells were seeded in 6-well plates and infected at an MOI of 1 with300 μl of DENV2-NGC. As a positive control for inhibition of viralfusion, DENV2-NGC was pre-incubated at 37° C. for 15 min with 5 μM ofDENV2 stem-peptide DENV2⁴¹⁹⁻⁴⁴⁷, which was provided by Aaron Schmidt andStephen Harrison (Schmidt et al., PLoS Pathogens (2010) 6:e1000851). Theplates were incubated with the virus for 1 hour at 37° C. and rockedevery 15 min. Unadsorbed virus was removed by a PBS wash, after which 2ml of media supplemented with DMSO or 2 μM of QL-XII-47 was added toeach well. After incubation at 37° C. for the indicated time, total RNAwas extracted from infected cells using TRIzol reagent followingmanufacturer's instructions (Life Technologies 15596-018). cDNA wasgenerated on 500 ng of total RNA using random hexamers to prime reversetranscription reactions using iScript cDNA Synthesis kit (Bio-Rad178-8890) following manufacturer's instructions. cDNAs were then diluted1:10 with nuclease-free water, and qPCR was performed with the cDNAusing the iQ SYBR Green Supermix kit (Bio-Rad 170-8880) according to themanufacturer's instructions. Reactions were run on a MyiQ iCycler(Bio-Rad) and analyzed with the MyiQ Optical System Software (Bio-Rad,Hercules, Calif.). qPCR conditions were an initial 95° C. for 5 min,followed by 40 cycles of 95° C. for 15 s and 60° C. for 30 s. Primersused were: DENV2 FW: 5′-AATATGCTGAAACGCGAGAGA-3′ (SEQ ID NO: 1); DENV2RV: 5′-GGGATTGTTAGGAAACGAAGG-3′(SEQ ID NO: 2); GAPDH FW:5′-GAGTCAACGGATTTGGTCGT-3′ (SEQ ID NO: 3); GAPDH RV:5′-TTGATTTTGGAGGGATCTCG-3′ (SEQ ID NO: 4). For each sample the DENV2 RNAcopy number was normalized to the GAPDH RNA copy number. The results areshown in FIG. 4A.

Huh7 cells were seeded in 24-well plates on cover slips and infected atan MOI of 10 with 100 μl of DENV2-NGC. Plates were incubated with thevirus for 1 hour at 37° C. and rocked every 15 min. Unadsorbed virus wasremoved by a PBS wash, and mock- or DENV2-infected cover slips werecollected to serve as a reference before addition of the small molecule.1 ml of media supplemented with DMSO or 2 μM of QL-XII-47 was added tothe remaining wells, and the cells were incubated at 37° C. Theremaining cover slips were collected at 3 h, 6 h, 9 h, 12 h, 15 h, and18 h post small molecule treatment. For each collection the cover slipswere fixed using 4% of paraformaldehyde. After incubation for 15 min atroom temperature, the cover slips were washed with PBS and kept at 4° C.until processing. Detection of DENV2 viral RNA in the cells was doneusing QuantiGene ViewRNA ISH Cell Assay kit (Panomics QVC0001) followingmanufacturer's instructions using a DENV2 specific probe set (PanomicsVF1-10744). The cover slips were mounted with ProLong Gold antifadereagent (Life Technologies P36930) prior to wide field imaging (nearestneighbors analysis) using a Marianas Spinning Disk confocal microscope.The results are shown in FIG. 4B.

Results

DENV genomic RNA persists at a relatively unchanged copy number in thepresence of QL-XII-47 and exhibits a punctate, cytoplasmic localization.In untreated cells, this signal decays and disappears by 12 hoursfollowed by abundant perinuclear genomic RNA at 18-24 hours due tosynthesis of new viral RNA genomes. In cells treated with a DENV-derivedpeptide that has been previously demonstrated to block viral fusion(Schmidt et al., PLoS Pathogens (2010) 6:e1000851), DENV RNA isdecreasing by 24 hours post-infection, presumably due to degradation ofthe virion in the lysosome (FIG. 4A). These data suggest that DENV entryis blocked at a “late entry step” that occurs after uptake of the virionbut prior to release of the genome from the nucleocapsid since the DENVappears to be protected from cytoplasmic nucleases.

Example 6. Antiviral Activities of QL-XII-47 Against Additional Viruses

To examine QL-XII-47 and QL-XII-56's spectrum of activity as antiviralagents, QL-XII-47 and QL-XII-56 were tested against a panel ofadditional viral pathogens using methods similar to what are describedin other Examples herein.

Potent inhibition of vesicular stomatitis virus (VSV), a negative-strandRNA virus unrelated to DENV, was observed; moreover, time-of-additionexperiments indicate that QL-XII-47 inhibits VSV at a step early in theVSV life cycle (FIG. 5A). Furthermore, imaging experiments usingfluorescently labeled VSV suggest that QL-XII-47 may interfere with astep late in VSV's entry process since it does not affect VSV attachmentor uptake. QL-XII-47 also potently inhibits VSV pseudotyped with Ebolaand rabies virus glycoproteins (EboV and RABV, respectively) (FIG. 5A).In general, the attachment, uptake, and fusion steps of pseudotypedvirus entry are expected to be directed by the Ebola and rabies virusglycoproteins, while the steps of endosomal escape, genome release, andinitiation of viral gene expression are believed to follow themechanisms utilized by wildtype VSV. Therefore, current data may suggestthat QL-XII-47 inhibits entry of Ebola and rabies viruses but may alsosuggest that QL-XII-47 acts at a post-fusion step of viral entry that isshared between wildtype VSV and its pseudotypes.

QL-XII-47 exhibits inhibitory activity against herpes simplex virus 1(HSV-1), human cytomegalovirus (HCMV), and poliovirus (FIGS. 5B to 5D)in assays that quantify viral entry and gene expression (HCMV andpoliovirus) or plaque formation (HSV-1). In less sensitive assaysmeasuring virus-induced cytopathic effects (CPE), QL-XII-47 was a modestinhibitor of Japanese Encephalitis virus (JEV) and Junin virus (FIGS. 5Eand 5F) but had no activity against influenza virus or vaccinia virus.It was noted that since QL-XII-47 is believed to act via a host target,the cell line and species type used for testing is likely to affect theobserved antiviral activity. On a similar note, although cytotoxicitywith QL-XII-47 at concentrations up to 20 μM in experiments using Huh7,Vero, BHK21, and 3T3 cell lines was not observed, single-digitmicromolar cytotoxicity was observed in Hela and 293 cell lines.Therefore, while it is known that QL-XII-47's activity against DENV andother viruses is not due to host cell death, on-going studies have beendesigned to clarify and to better understand QL-XII-47's range ofantiviral activity and cytotoxicity profile in additional cell lines.

Both QL-XII-47 and QL-XII-56 show inhibitory activity against Ebolaglycoprotein (EBOV) (FIGS. 5G to 5J), Marburg virus (MARV) (FIGS. 5K to5N), Junin virus (JUNV) (FIGS. 5O and 5P), Lassa fever virus (LASV)(FIGS. 5Q and 5R), Venezuelan equine encephalitis virus (VEEV) (FIGS. 5Sand 5T), and Rift Valley fever virus (RVFV) (FIGS. 5U and 5V).

Example 7. RNAi-Mediated Depletion Experiments and Cell-Based AssaysShowing Bmx is not the Target Mediating QL-XII-47's Anti-DENV ActivityMethods

Huh7 cells were seeded in 24-well plates and concomitantly transfectedwith 100 nM of non-targeting (Sigma SIC001) or Bmx MISSION siRNAs (Sigmapool of SASI_Hs01_00019552, SASI_Hs01_00019553 and SASI_Hs01_00185298)using Lipofectamine RNAiMAX (Life Technologies 13778-075) and followingthe manufacturer's instructions. At 48 hours post-siRNA transfection,the cells were infected at an MOI of 1 with 100 μl of DENV2-NGC. Theplates were incubated with the virus for 1 hour at 37° C. and rockedevery 15 min. Unadsorbed virus was removed by a PBS wash, after which500 μl of DMEM supplemented with 2% FBS was added to each well. Afterincubation at 37° C. for 24 hours, the supernatants were collected forDENV2 titration using a focus forming assay, as described in Example 3.The results are shown in FIG. 6A.

The results shown in FIG. 6B were obtained by using the methodsdescribed in Example 3.

Results

Extensive kinase profiling of QL-XII-47 using biochemical and chemicalproteomic approaches such as KiNativ50 identified two Tec-familykinases, Bmx and Btk, as potent (IC₅₀ 7 nM) biochemical and cellulartargets of QL-XII-47. However, data indicate that neither of thesekinases is likely responsible for the potent anti-DENV activity of thecompound. Btk is a B lymphocyte-specific kinase and not expressed in theHuh7 cells used in the DENV experiments. While Bmx is known to be morewidely expressed, it was not detected in Huh7 by microarray expressionprofiling (see, e.g., biogps.org/#goto=genereport&id=660) or by Westernblot. Moreover, RNAi-mediated depletion of any low level Bmx expressionhad no effect on DENV replication (FIG. 6A). In addition, DENV is notinhibited by PCI-32765, another covalent inhibitor of Bmx and Btk (IC₅₀0.5 nM) (Honigberg et al., Proc. Nat. Acad. Sci. USA (2010)107:13075-13080) (FIG. 6B).

Example 8. Identification of Candidate Targets by “Click” Chemistry

To identify cellular proteins that are covalently targeted by QL-XII-47,a chemical proteomics approach using “click-chemistry” was performed.

QL-XII-47AL, an analog of QL-XII-47 modified with an alkyne group, wasdesigned which can undergo a copper-catalyzed cyclo-addition reactionwith an azide group (the so-called “click” reaction) and which retainsthe antiviral activity of QL-XII-47 (FIGS. 8A and 8B). The advantage of“click-chemistry” relative to conventional affinity chromatography isthat the QL-XII-47AL can be introduced to living cells infected withDENV thereby allowing bond formation under more physiologicalconditions. Subsequent cell lysis and reaction withdesthiobiotin-PEG-azide, followed by capture with streptavidin beads,trypsin digestion, and mass-spectrometry allows identification ofpotential target proteins. This approach is powerful because both hostand viral targets can be identified. Several potential targets have beenidentified using this approach (FIGS. 8A and 8B). Analysis of the siteslabeled demonstrates that many of these targets were modified on acysteine residue located in the catalytic site, suggesting thatQL-XII-47 is likely to disable enzymatic activity as predicted. Thisapproach may be used to identify candidate targets of QL-XII-47 andother inhibitors and to generate “clickable” derivatives of compoundsthat are structurally similar to QL-XII-47 but that do not inhibit DENV(e.g., QL-XI-76, see FIGS. 2A and 2G). Parallel proteomic analysis usingthe negative controls should help to eliminate candidates thatcovalently react with the inhibitor but that are not relevant toantiviral activity.

Molecular modeling may also be performed of the inventive compoundsbound to the targets identified by the click-chemistry pull-downexperiments in order to rationalize target-based SAR and to guidepotential chemical modifications. For example, QL-XII-47AL covalentlymodifies Cys302 of aldehyde dehyrodenase 1 (ALH1), and molecular dockingsuggests that QL-XII-47 fits well into the nicotinamide binding site ofALDH1 with the acrylamide perfectly poised to react with Cys302 (FIGS.9A and 9B). Furthermore, the methyl pyrazole side-chain of QL-XII-47 ispredicted to form a key hydrogen bond with the backbone NH of Cys302 andCys303, an interaction that is lost in negative control compoundQL-XI-76, which contains a non-hydrogen bond competent furan at thisposition. Based on these models, compounds may be designed that willdisrupt key interactions, and this will allow for establishing whether acorrelation exists between inhibition of a potential target (such asALDH1) and the anti-DENV activity of the compound. This is a classicalapproach to establishing the relevance of a particular target that iscomplementary to the RNAi.

In sum, a class of substituted quinolones, exemplified by QL-XII-47, hasbeen discovered to show potent anti-DENV activity in vitro. QL-XII-47causes a >3-log₁₀ unit drop in viral titer at single-digit micromolarconcentrations with no observed cytotoxicity. QL-XII-47 has activityagainst strains representative of all four DENV serotypes (DENV1-DENV4)as well as against Kunjin virus (KUNV) and Japanese Encephalitis Virus(JEV), related members of the Flaviviridae family. In addition, it hasbeen found that QL-XII-47 exhibits activity against vesicular stomatitisvirus (VSV) and VSV expressing rabies or Ebola glycoproteins, and otherviruses, suggesting that QL-XII-47 may have broad spectrum activityagainst additional Category A, B, or C viral pathogens. Preliminaryexperiments suggest strongly that QL-XII-47 inhibits a step early in theDENV life cycle by covalently modifying a reactive cysteine residue in ayet-to-be-identified host factor. QL-XII-47 (EC₉₀ 400 nM) is more thanten-fold more potent than 7-DMA, and thus it is believed that inhibitorssimilar to QL-XII-47 will have commensurately greater decreases in viralburden and the inflammatory cytokine response.

Example 9. QL-XII-47 Inhibited DENV2 Viral Production

Huh7 cells were infected with DENV2 virus at MOI of about 1 during onehour at 37° C. Then, at time (t)=0, the cells were rinsed once with PBSand then medium (DMEM supplemented with 2% FBS and either 4 μM QL-XII-47or DMSO) was added. At each indicated time, supernatants were harvestedfor titration in FFU/ml, cell lysed for RNA extraction and reversetranscription quantitative polymerase chain reaction (RTqPCR).Additional duplicates were done in parallel for Western blotting.

The results, shown in FIGS. 10A to 10C, indicate that QL-XII-47inhibited DENV2 viral production. Values of FFU (focus forming units)/mlwere decreased for the infected cells treated with QL-XII-47 after about12 hours of infection compared to the infected cells not treated with acompound of the invention (FIG. 10A). Viral count was also decreased forthe infected cells treated with QL-XII-47 after about 12 hours ofinfection compared to the infected cells not treated with a compound ofthe invention (FIG. 10B).

Example 10. QL-XII-47 and QL-XII-56 Inhibited DENV2 Translation

Plasmid pDV2-Fluc(WT) or pDV2-FlucGDV encode dengue virus serotype 2RNAs in which a luciferase reporter gene replaces most of the genesencoding core, prM, and E. In vitro transcripts of the wildtype replicon(WT) and a mutant that cannot replicate RNA due to mutations in theactive site of the viral polymerase (GDV mutant) were produced. Huh7cells were electroporated with the respective DV2-replicon RNAs.Directly after electroporation cells are incubated with the indicateddrug (QL-XII-47 2 μM, cycloheximide 30 μg/ml, MPA 5 μM). At theindicated time post-electroporation, luminescence was measured as amarker of translation. For the WT construct, luc activity at an earlytime point (12 hours or less) reflect translation of the input RNAdelivered by electroporation; luc activity at later time points reflectsluc translated from both input and newly synthesized replicon RNA. Sincethe GDV mutant cannot synthesize new viral RNA, luciferase activityobserved at all time points is the product of the input RNA delivered byelectroporation.

Linearized plasmid was used for in vitro Transcription (IVT) and capped(no capping for IRES-EMC-Fluc). Those RNAs are then electroporated inHuh7 cells. Directly after electroporation cells are incubated with theindicated compound (QL-XII-47 (2 μM), cycloheximide (30 μg/ml), ormycophenolic acid (MPA, 5 μM)). At the indicated time postelectroporation, cells were washed with PBS and lysed using the adaptedlysis buffer (Firefly, Renilla or Dual lysis buffer from Promega).Luminescence is measured using Firefly, Renilla or Dual kit followingrecommendations, and read on Envision instrument. The results are shownin FIG. 11.

Huh7 cells were electoporated with IVTs of DENV2-Fluc(WT) or DENV2-Fluc(GDV). Some cells were treated with the indicated compound (QL-XII-47 (2μM), QL-XII-56 (2 μM), or cycloheximide (CHX, 30 μg/ml)), and othercells were not treated with the indicated compound. Firefly Luciferaseluminescence was measured at indicated times. The results are shown inFIGS. 12A to 12B and Table 1. FIG. 12A shows the luciferase activitymeasured at 6 hours post-electroporation for Huh7 cells electroporatedwith the wildtype (WT) or mutant (MUT) replicon RNAs and then treatedwith 2 μM QL-XII-47, 2 μM QL-XII-56, 30 μg/mL cycloheximide (CHX) asgeneral inhibitor of translation, or DMSO as a negative control.Luciferase at this time point is due to translation template by theinput RNA electroporated into cells. Reduced luciferase activity for thecells treated with QL-XII-47, QL-XII-56, and cycloheximide indicatesreduced translation of both WT and GVD replicons. FIG. 12B showsluciferase activity measured at the indicated time point for cellselectroporated with the WT or GVD replicon RNA and then treated withDMSO, QL-XII-47, QL-XII-56, or cycloheximide as indicated. For the WTreplicon, luciferase at early time points (6 h) reflects translation ofthe input RNA; luciferase activity at later time points (24, 48, 72 h)reflects translation template by newly synthesized RNA. For the GVDmutant, which cannot replicate viral RNA due to mutation of the viralpolymerase active site, luciferase at all time points reflects the inputRNA alone. The data in column 3 indicate the p-value calculated by thestudent's t-test for comparison of the compound-treated samples with theDMSO-treated negative control, demonstrating the statisticalsignificance of the inhibition of viral RNA translation by QL-XII-56,QL-XII-47, and CHX.

TABLE 1 P-values of compound-treated samples P-value for student's ttest comparison of compound-treated to untreated negative control(Cap-driven) GDV QL-XII-56 0.000441 QL-XII-47 0.000121 CHX 0.000186 WTQL-XII-56 0.000181 QL-XII-47 0.000039 CHX 0.000111

These results indicate that QL-XII-47 and QL-XII-56 inhibited DENV2 RNAtranslation.

Example 11. QL-XII-47 and QL-XII-56 Inhibited Encephalomyocarditis Virus(EMCV) IRES-Dependant Translation

Huh7 cells were electroporated with in vitro transcripts of the DV2 WTand GVD replicon RNAs or an RNA encoding a luciferase reporter under thecontrol of the encephalomyocarditis virus (EMCV) IRES element. Cellswere treated QL-XII-47 or a combination of cycloheximide (CHX) as ageneral inhibitor of translation and mycophenolic acid (MPA) as aninhibitor of viral RNA replication or with DMSO as a negative controlimmediately post-electroporation. Luciferase activity was measured at 6hours post-electroporation as a measure of the translation of thedifferent RNAs. Reduced luciferase activity indicates reduction intranslation of the RNA in that sample. The data indicate that QL-XII-47reduces translation of WT and GVD DV replicon RNAs as well astranslation of the EMCV IRES; moreover, the reduction in translation iscomparable in magnitude to that caused by the CHX/MPA positive control.

In order investigate Cap-dependent or IRES-dependent translation of EMCVwithout DENV2 backbone, plasmid pFR-CrPV was used. pFR-CrPV, a plasmidencoding the bicistronic expression construct used to test cap-drivenand IRES-driven translation from the same RNA template. Fireflyluciferase translation is cap-driven while renilla luciferase expressionis driven by the IRES element of the Cricket paralysis virus (CrPV).When transfected into cells, RNA pol II drives transcription to producethe bicistronic RNA. Dual luciferase assay can be performed to measuretranslation of both cap-dependent and IRES-driven translation. Theplasmid was previously published, seewww.pnas.org/content/early/2012/11/14/1216454109.abstract. Huh7 cellswere retrotransfected with pFR-CrPV. 28 h post transfection, the cellswere treated with the indicated compound (QL-XII-47 (2 μM), QL-XII-56 (2μM), CHX (30 μg/ml)) for an additional 24 h. The cells were washed oncewith PBS and lysed with dual luciferase assay buffer. The results areshown in FIGS. 15A and 15B and Table 2. The data in column 3 of Table 2indicate the value calculated by the student's t-test for comparison ofthe compound-treated samples with the DMSO-treated negative control,demonstrating the statistical significance of the inhibition oftranslation by QL-XII-56, QL-XII-47, and CHX.

TABLE 2 Statistical analysis of the reduction in cap- dependent andIRES-dependent translation p-value for student's p-value for student'st-test comparison of t-test comparison of compound-treated to DMSOcompound-treated to DMSO negative control(Cap- negative control(IRES-driven translation) driven translation QL-XII-47 0.019667 0.009291QL-XII-56 0.026517 0.026662 CHX 0.013357 0.001974 Mock 0.00817 0.001656

These results indicate that QL-XII-47 and QL-XII-56 inhibited EMCV-IRESdependant translation in Huh7 cells.

Example 12. QL-XII-47 Biotin Test

Huh7 cells were infected with DENV2 virus at an MOI of about 1 duringone hour at 37° C. Then, at time (t)=0, the cells were rinsed once withPBS. The cells were treated with the indicated compound (QL-XII-47 orQL-XII-47 biotin) for 24 or 48 h. Supernatants were harvested fortitration in FFU/ml, cell lysed for RNA extraction and RTqPCR. Thestructure of QL-XII-47 biotin is of the following formula:

The results, shown in FIG. 16, indicate that QL-XII-47-biotin hassignificantly reduced inhibitory activity against dengue virus.

Example 13. Test of the Effects of RNAi-Mediated Depletion of Prdx1

Huh 7 cells were retrotransfected with siRNA Prdx1 and plated in 12 wellplates. At 48 h, the cells were infected with DENV2 virus at an MOI ofabout 1 during one hour at 37° C. Some cells were treated for 24 h with4 μM of QL-XII-47 or QL-XII-56, and other cells were not so treated.Supernatant were harvested for titration and cells lysed for Westernblotting.

The results are shown in FIGS. 17A to 17B. FIG. 17A shows thatRNAi-mediated depletion of Prdx-1 does not reduce steady-stateexpression of dengue NS3 protein (left); moreover, combination treatmentof cells with siRNAs against Prdx-1 and QL-XII-47 does not reducesteady-state expression of NS3 beyond what is observed with QL-XII-47alone. FIG. 17B shows the quantitation of infectious viral particlesreleased to the culture supernatants at 24 hours post-infection showingthat RNAi-mediated depletion of Prdx-1 does not appear to inhibit denguevirus.

Example 14. QL-XII-47 and QL-XII-56 Inhibited Vesicular Stomatitis Virus(VSV)

Vero cells were infected at an MOI of about 1 with VSV for 1 h at 37° C.in Earle's balanced salt solution (EBSS). At t=0, the cells were washedonce with PBS and then medium (DMEM with 10% fetal bovine serum)containing the indicated compounds (N-(4 hydroxyphenyl)retinamide (4HPR,5 μM), QL-XII-47 (4 μM), or QL-XII-56 (4 μM)) was added. At 6 h postinfection (6 hpi), supernatant were harvested for titration, and thecells were lysed for RNA extraction and RTqPCR.

The results, shown in FIGS. 18A and 18B, demonstrate that QL-XII-47 andQL-XII-56 inhibited VSV.

Example 15. QL-XII-47 and QL-XII-56 Inhibited Poliovirus Type 1 (PV1)

Vero cells were infected at an MOI of about 1 with PV1 for 1 h at 37° C.in Earle's balanced salt solution (EBSS). At t=0, the cells were washedonce with PBS and then medium (DMEM with 10% fetal bovine serum)containing the indicated compound (N-(4 hydroxyphenyl)retinamide (4HPR,5 μM), QL-XII-47 (4 μM), or QL-XII-56 (4 μM)) was added. At 6 h postinfection (6 hpi), supernatant were harvested for titration, and thecells were lysed for RNA extraction and RTqPCR.

The results, shown in FIGS. 19A and 19B, demonstrate that QL-XII-47 andQL-XII-56 inhibited PV1.

Example 16. Summary of FFA, RVP, Cytotoxicity Evaluation of theExemplary Compounds

Table 3 lists the results of FFA and RVP evaluation of the exemplarycompounds.

TABLE 3 FFA and RVP Evaluatin of Exemplary Compounds FFA RVP RVPCompound Cytotox- (2 or (2 uM (2.5 uM No. icity 2.5 uM) screen)pretreat) QL-XI-57 — — 2 — QL-XI-55 NO 6 5 4 QL-VI-50 — 1 — — QL-XI-65at 10 uM 77 6 12  QL-V-85 — 1 — — QL-IX-97 — 1 — — QL-X-39 — 1 — —QL-X-132 — — 1 — QL-XI-99 — — 1 — QL-XI-100 — — 2 — QL-XI-75 — — 1 —QL-XII-01 — — 1 — QL-XII-03 — — 1 — QL-XII-37 — — 1 — QL-XII-40 — — 1 —QL-XII-58 — 1 1 — QL-XII-61 — 1 1 — QL-XI-76 — 1 1 — QL-XII-63 — — 2 —QL-XII-66 — — 2 — QL-XII-57 — 1 2 — QL-XI-77 NO 1 2 1 QL-X-138 NO 61 3 3QL-X-134 NO 107 2 4 QL-XII-56 NO 62 1 6 QL-XII-115 NO 36000 5 43 QL-XII-54 NO 36000 70  95  QL-XII-38 — — 1 — QL-XII-45 — — 1 — QL-XII-46— — 1 — QL-XII-91 — — 1 — QL-XII-48 — — 2 — QL-XII-50 — — 2 — QL-XII-51 at 5 uM 36000 2 — QL-XII-47 NO 3600 19  106  QL-XII-44 at 10 uM 36000 8125 

OTHER EMBODIMENTS

The foregoing has been a description of certain non-limiting embodimentsof the invention. Those of ordinary skill in the art will appreciatethat various changes and modifications to this description may be madewithout departing from the spirit or scope of the present invention, asdefined in the following claims.

All publications, including but not limited to journal articles, books,patents, and patent applications, cited in this specification are hereinincorporated by reference as if each individual publication werespecifically and individually indicated to be incorporated by referenceherein as though fully set forth.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof; wherein: Ring A is heteroaryl; each instance of R^(A)is independently selected from the group consisting of hydrogen,halogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN,—C(═NR^(A1))R^(A1), —C(═NR^(A1))OR^(A1), —C(═NR^(A1))SR^(A1),—C(═NR^(A1))N(R^(A1))₂, —C(═O)NR^(A1)—, —NR^(A1)C(═O)—, —C(═O)R^(A1),—C(═S)R^(A1), —C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A1))₂, —NO₂, —N₃,—N(R^(A1))₃ ⁺F⁻, —N(R^(A1))₃ ⁺Cl⁻, —N(R^(A1))₃ ⁺Br⁻, —N(R^(A1))₃ ⁺I⁻,—N(OR^(A1))R^(A1), —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1),—NR^(A1)C(═O)SR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)C(═S)R^(A1),—NR^(A1)C(═S)OR^(A1), —NR^(A1)C(═S)SR^(A1), —NR^(A1)C(═S)N(R^(A1))₂,—NR^(A1)C(═NR^(A1))R^(A1), —NR^(A1)C(═NR^(A1))OR^(A1),—NR^(A1)C(═NR^(A1))SR^(A1), —NR^(A1)C(═NR^(A1))N(R^(A1))₂,—NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)₂OR^(A1), —NR^(A1)S(═O)₂SR^(A1),—NR^(A1)S(═O)₂N(R^(A1))₂, —NR^(A1)S(═O)R^(A1), —NR^(A1)S(═O)OR^(A1),—NR^(A1)S(═O)SR^(A1), —NR^(A1)S(═O)N(R^(A1))₂, —NR^(A1)P(═O),—NR^(A1)P(═O)₂, —NR^(A1)P(═O)(R^(A1))₂, —NR^(A1)P(═O)R^(A1)(OR^(A1)),—NR^(A1)P(═O)(OR^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —OC(═NR^(A1))R^(A1), —OC(═NR^(A1))OR^(A1),—OC(═NR^(A1))N(R^(A1))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A1))₂, —ON(R^(A1))₂, —OS(═O)R^(A1), —OS(═O)OR^(A1),—OS(═O)SR^(A1), —OS(═O)N(R^(A1))₂, —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),—OS(═O)₂SR^(A1), —OS(═O)₂N(R^(A1))₂, —OP(═O)₂, —OP(═O)(R^(A1))₂,—OP(═O)R^(A1)(OR^(A1)), —OP(═O)(OR^(A1))₂, —OP(═O), —OP(R^(A1))₂,—OPR^(A1)(OR^(A1)), —OP(OR^(A1))₂, —OSi(R^(A1))₃, —OSi(R^(A1))₂OR^(A1),—OSi(R^(A1))(OR^(A1))₂, —OSi(OR^(A1))₃, —SSR^(A1), —S(═O)R^(A1),—S(═O)OR^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1),—S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A1))₂, —P(R^(A1))₂, —PR^(A1)(OR^(A1)), —P(OR^(A1))₂, —P(═O),—P(═O)(R^(A1))₂, —P(═O)(OR^(A1))₂, —P(═O)R^(A1)(OR^(A1)), —P(═O)₂,—B(R^(A1))₂, —B(OR^(A1))₂, —BR^(A1)(OR^(A1)), —Si(R^(A1))₃,—Si(R^(A1))₂OR^(A1), —SiR^(A1)(OR^(A1))₂, and —Si(OR^(A))₃, wherein eachoccurrence of R^(A1) is independently selected from the group consistingof hydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, anitrogen protecting group when attached to a nitrogen atom, an oxygenprotecting group when attached to an oxygen atom, a sulfur protectinggroup when attached to a sulfur atom, or two R^(A1) groups are joined toform an optionally substituted heterocyclic ring; k is 0, 1, 2, 3, 4, or5; Ring C is a carbocyclic, heterocyclic, aryl, or heteroaryl ring; eachinstance of R^(C) is independently selected from the group consisting ofhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —OR^(C1), —N(R^(C1))₂,—SR^(C1), —CN, —C(═NR^(C1))R^(C1), —C(═NR^(C1))OR^(C1),—C(═NR^(C1))SR^(C1), —C(═NR^(C1))N(R^(C1))₂, —C(═O)R^(C1), —C(═S)R^(C1),—C(═S)OR^(C1), —C(═S)SR^(C1), —C(═S)N(R^(C1))₂, —NO₂, —N₃, —N(R^(C1))₃⁺F⁻, —N(R^(C1))₃ ⁺Cl⁻, —N(R^(C1))₃ ⁺Br⁻, —N(R^(C1))₃ ⁺I⁻,—N(OR^(C1))R^(C1), —NR^(C1)C(═O)R^(C1), —NR^(C1)C(═O)OR^(C1),—NR^(C1)C(═O)SR^(C1), —NR^(C1)C(═O)N(R^(C1))₂, —NR^(C1)C(═S)R^(C1),—NR^(C1)C(═S)OR^(C1), —NR^(C1)C(═S)SR^(C1), —NR^(C1)C(═S)N(R^(C1))₂,—NR^(C1)C(═NR)R^(C1), —NR^(C1)C(═NR^(C1))OR^(C1),—NR^(C1)C(═NR^(C1))SR^(C1), —NR^(C1)C(═NR^(C1))N(R^(C1))₂,—NR^(C1)S(═O)₂R^(C1), —NR^(C1)S(═O)₂OR^(C1), —NR^(C1)S(═O)₂SR^(C1),—NR^(C1)S(═O)₂N(R^(C1))₂, —NR^(C1)S(═O)R^(C1), —NR^(C1)S(═O)OR^(C1),—NR^(C1)S(═O)SR^(C1), —NR^(C1)S(═O)N(R^(C1))₂, —NR^(C1)P(═O),—NR^(C1)P(═O)₂, —NR^(C1)P(═O)(R^(C1))₂, —NR^(C1)P(═O)R^(C1)(OR^(C1)),—NR^(C1)P(═O)(OR^(C1))₂, —OC(═O)R^(C1), —OC(═O)OR^(C1), —OC(═O)SR^(C1),—OC(═O)N(R^(C1))₂, —OC(═NR^(C1))R^(C1), —OC(═NR^(C1))OR^(C1),—OC(═NR^(C1))N(R^(C1))₂, —OC(═S)R^(C1), —OC(═S)OR^(C1), —OC(═S)SR^(C1),—OC(═S)N(R^(C1))₂, —ON(R^(C1))₂, —OS(═O)R^(C1), —OS(═O)OR^(C1),—OS(═O)SR^(C1), —OS(═O)N(R^(C1))₂, —OS(═O)₂R^(C1), —OS(═O)₂OR^(C1),—OS(═O)₂SR^(C1), —OS(═O)₂N(R^(C1))₂, —OP(═O)₂, —OP(═O)(R^(C1))₂,—OP(═O)R^(C1)(OR^(C1)), —OP(═O)(OR^(C1))₂, —OP(═O), —OP(R^(C1))₂,—OPR^(C1)(OR^(C1)), —OP(OR^(C1))₂, —OSi(R^(C1))₃, —OSi(R^(C1))₂OR^(C1),—OSi(R^(C1))(OR^(C1))₂, —OSi(OR^(C1))₃, —SSR^(C1), —S(═O)R^(C1),—S(═O)OR^(C1), —S(═O)N(R^(C1))₂, —S(═O)₂R^(C1), —S(═O)₂OR^(C1),—S(═O)₂N(R^(C1))₂, —SC(═O)R^(C1), —SC(═O)OR^(C1), —SC(═O)SR^(C1),—SC(═O)N(R^(C1))₂, —SC(═S)R^(C1), —SC(═S)OR^(C1), —SC(═S)SR^(C1),—SC(═S)N(R^(C1))₂, —P(R^(C1))₂, —PR^(C1)(OR^(C1)), —P(OR^(C1))₂, —P(═O),—P(═O)(R^(C1))₂, —P(═O)(OR^(C1))₂, —P(═O)R^(C1)(OR^(C1)), —P(═O)₂,—B(R^(C1))₂, —B(OR^(C1))₂, —BR^(C1)(OR^(C1)), —Si(R^(C1))₃,—Si(R^(C1))₂OR^(C1), —SiR^(C1)(OR^(C1))₂, and —Si(OR^(C1))₃, whereineach occurrence of R^(C1) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(C1) groups are joined to form an optionally substituted heterocyclicring or optionally substituted heteroaryl ring; n is 0, 1, 2, 3, or 4; Lis a bond or an optionally substituted, branched or unbranched C₁₋₆hydrocarbon chain; R^(D) is any one of Formulae (i-1)-(i-43):

wherein: each instance of R^(D1) is independently hydrogen, halogen,acyl, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a),—CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a),—C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a),—C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a),—C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1a), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a) groups arejoined to form an substituted or unsubstituted heterocyclic ring; eachinstance of R^(D2) is independently hydrogen, halogen, acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO₂,—OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a)CH₂N(R^(D2a))₂,—CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a),—C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a),—C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a),—C(═NR^(D2a))SR^(D2a), and —C(═NR^(D2a))N(R^(D2a))₂, wherein eachoccurrence of R^(D2a) is independently hydrogen, acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, or two R^(D2a) groupsare joined to form an substituted or unsubstituted heterocyclic ring;each instance of R^(D3) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a),—CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a),—C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a),—C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring; R^(D4) is a leavinggroup selected from the group consisting of —Br, —Cl, —I, and—OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each instance of X¹ isindependently a bond, —C(═O)—, —SO₂—, —NR^(D5)—, optionally substitutedalkylene, or optionally substituted heteroarylene, wherein R^(D5) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; each instance of Yis independently O, S, or NR^(D6), wherein R^(D6) is hydrogen, C₁₋₆alkyl, or a nitrogen protecting group; and each instance of z and z₁ isindependently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
 2. A compoundof Formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof; wherein: Ring A is aryl, arylalkenyl, or heteroaryl;each instance of R^(A) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═NR^(A1))R^(A1),—C(═NR^(A1))OR^(A1), —C(═NR^(A1))SR^(A1), —C(═NR^(A1))N(R^(A1))₂,—C(═O)NR^(A1)—, —NR^(A1)C(═O)—, —C(═O)R^(A1), —C(═S)R^(A1),—C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A1))₂, —NO₂, —N₃, —N(R^(A1))₃⁺F⁻, —N(R^(A1))₃ ⁺Cl⁻, —N(R^(A1))₃ ⁺Br⁻, —N(R^(A1))₃ ⁺I⁻,—N(OR^(A1))R^(A1), —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1),—NR^(A1)C(═O)SR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)C(═S)R^(A1),—NR^(A1)C(═S)OR^(A1), —NR^(A1)C(═S)SR^(A1), —NR^(A1)C(═S)N(R^(A1))₂,—NR^(A1)C(═NR^(A1))R^(A1), —NR^(A1)C(═NR^(A1))OR^(A1),—NR^(A1)C(═NR^(A1))SR^(A1), —NR^(A1)C(═NR^(A1))N(R^(A1))₂,—NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)₂OR^(A1), —NR^(A1)S(═O)₂SR^(A1),—NR^(A1)S(═O)₂N(R^(A1))₂, —NR^(A1)S(═O)R^(A1), —NR^(A1)S(═O)OR^(A1),—NR^(A1)S(═O)SR^(A1), —NR^(A1)S(═O)N(R^(A1))₂, —NR^(A1)P(═O),—NR^(A1)P(═O)₂, —NR^(A1)P(═O)(R^(A1))₂, —NR^(A1)P(═O)R^(A1)(OR^(A1)),—NR^(A1)P(═O)(OR^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —OC(═NR^(A1))R^(A1), —OC(═NR^(A1))OR^(A1),—OC(═NR^(A1))N(R^(A1))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A1))₂, —ON(R^(A1))₂, —OS(═O)R^(A1), —OS(═O)OR^(A1),—OS(═O)SR^(A1), —OS(═O)N(R^(A1))₂, —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),—OS(═O)₂SR^(A1), —OS(═O)₂N(R^(A1))₂, —OP(═O)₂, —OP(═O)(R^(A1))₂,—OP(═O)R^(A1)(OR^(A1)), —OP(═O)(OR^(A1))₂, —OP(═O), —OP(R^(A1))₂,—OPR^(A1)(OR^(A1)), —OP(OR^(A1))₂, —OSi(R^(A1))₃, —OSi(R^(A1))₂OR^(A1),—OSi(R^(A1))(OR^(A1))₂, —OSi(OR^(A1))₃, —SSR^(A1), —S(═O)R^(A1),—S(═O)OR^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A1),—S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A1))₂, —P(R^(A1))₂, —PR^(A1)(OR^(A1)), —P(OR^(A1))₂, —P(═O),—P(═O)(R^(A1))₂, —P(═O)(OR^(A1))₂, —P(═O)R^(A1)(OR^(A1)), —P(═O)₂,—B(R^(A1))₂, —B(OR^(A1))₂, —BR^(A1)(OR^(A1)), —Si(R^(A1))₃,—Si(R^(A1))₂OR^(A1), —SiR^(A1)(OR^(A1))₂, and —Si(OR^(A1))₃, whereineach occurrence of R^(A1) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(A1) groups are joined to form an optionally substituted heterocyclicring; k is 0, 1, 2, 3, 4, or 5; Ring C is a carbocyclic, heterocyclic,aryl, or heteroaryl ring; each instance of R^(j1), R^(j2), R^(j3), andR^(C) is independently selected from the group consisting of hydrogen,halogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —OR^(C1), —N(R^(C1))₂, —SR^(C1), —CN,—C(═NR^(C1))R^(C1), —C(═NR^(C1))OR^(C1), —C(═NR^(C1))SR^(C1),—C(═NR^(C1))N(R^(C1))₂, —C(═O)R^(C1), —C(═S)R^(C1), —C(═S)OR^(C1),—C(═S)SR^(C1), —C(═S)N(R^(C1))₂, —NO₂, —N₃, —N(R^(C1))₃ ⁺F⁻, —N(R^(C1))₃⁺Cl⁻, —N(R^(C1))₃ ⁺Br⁻, —N(R^(C1))₃ ⁺F⁻, —N(OR^(C1))R^(C1),—NR^(C1)C(═O)R^(C1), —NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1),—NR^(C1)C(═O)N(R^(C1))₂, —NR^(C1)C(═S)R^(C1), —NR^(C1)C(═S)OR^(C1),—NR^(C1)C(═S)SR^(C1), —NR^(C1)C(═S)N(R^(C1))₂,—NR^(C1)C(═NR^(C1))R^(C1), —NR^(C1)C(═NR^(C1))OR^(C1),—NR^(C1)C(═NR^(C1))SR^(C1), —NR^(C1)C(═NR^(C1))N(R^(C1))₂,—NR^(C1)S(═O)₂R^(C1), —NR^(C1)S(═O)₂OR^(C1), —NR^(C1)S(═O)₂SR^(C1),—NR^(C1)S(═O)₂N(R^(C1))₂, —NR^(C1)S(═O)R^(C1), —NR^(C1)S(═O)OR^(C1),—NR^(C1)S(═O)SR^(C1), —NR^(C1)S(═O)N(R^(C1))₂, —NR^(C1)P(═O),—NR^(C1)P(═O)₂, —NR^(C1)P(═O)(R^(C1))₂, —NR^(C1)P(═O)R^(C1)(OR^(C1)),—NR^(C1)P(═O)(OR¹)₂, —OC(═O)R^(C1), —OC(═O)OR^(C1), —OC(═O)SR^(C1),—OC(═O)N(R^(C1))₂, —OC(═NR^(C1))R^(C1), —OC(═NR^(C1))OR^(C1),—OC(═NR^(C1))N(R^(C1))₂, —OC(═S)R^(C1), —OC(═S)OR^(C1), —OC(═S)SR^(C1),—OC(═S)N(R^(C1))₂, —ON(R^(C1))₂, —OS(═O)R^(C1), —OS(═O)OR^(C1),—OS(═O)SR^(C1), —OS(═O)N(R^(C1))₂, —OS(═O)₂R^(C1), —OS(═O)₂OR^(C1),—OS(═O)₂SR^(C1), —OS(═O)₂N(R^(C1))₂, —OP(═O)₂, —OP(═O)(R^(C1))₂,—OP(═O)R^(C1)(OR^(C1)), —OP(═O)(OR^(C1))₂, —OP(═O), —OP(R^(C1))₂,—OPR^(C1)(OR^(C1)), —OP(OR^(C1))₂, —OSi(R^(C1))₃, —OSi(R^(C1))₂OR^(C1),—OSi(R^(C1))(OR^(C1))₂, —OSi(OR^(C1))₃, —SSR^(C1), —S(═O)R^(C1),—S(═O)OR^(C1), —S(═O)N(R^(C1))₂, —S(═O)₂R^(C1), —S(═O)₂OR^(C1),—S(═O)₂N(R^(C1))₂, —SC(═O)R^(C1), —SC(═O)OR^(C1), —SC(═O)SR^(C1),—SC(═O)N(R^(C1))₂, —SC(═S)R^(C1), —SC(═S)OR^(C1), —SC(═S)SR^(C1),—SC(═S)N(R^(C1))₂, —P(R^(C1))₂, —PR^(C1)(OR^(C1)), —P(OR^(C1))₂, —P(═O),—P(═O)(R^(C1))₂, —P(═O)(OR^(C1))₂, —P(═O)R^(C1)(OR^(C1)), —P(═O)₂,—B(R^(C1))₂, —B(OR^(C1))₂, —BR^(C1)(OR^(C1)), —Si(R^(C1))₃,—Si(R^(C1))₂OR^(C1), —SiR^(C1)(OR^(C1))₂, and —Si(OR^(C1))₃, whereineach occurrence of R^(C)d is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(C1) groups are joined to form an optionally substituted heterocyclicring or optionally substituted heteroaryl ring; n is 0, 1, 2, 3, or 4; Lis a bond or an optionally substituted, branched or unbranched C₁₋₆hydrocarbon chain; R^(D) is any one of Formulae (i-1)-(i-43):

wherein: each instance of R^(D1) is independently hydrogen, halogen,acyl, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a),—CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a),—C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a),—C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a),—C(═NR^(D1a))OR^(D1a), —C(═NR^(D1a))SR^(D1), or—C(═NR^(D1a))N(R^(D1a))₂, wherein each occurrence of R^(D1a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D1a), groups arejoined to form an substituted or unsubstituted heterocyclic ring; eachinstance of R^(D2) is independently hydrogen, halogen, acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —CN, —NO₂,—OR^(D2a), —N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a), —CH₂N(R^(D2a))₂,—CH₂SR^(D2a), —C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a),—C(═O)N(R^(D2a))₂, —C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a),—C(═S)N(R^(D2a))₂, —C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a),—C(═NR^(D2a))SR^(D2a), and —C(═NR^(D2a))N(R^(D2a))₂, wherein eachoccurrence of R^(D2a) is independently hydrogen, acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl, or two R^(D2a) groupsare joined to form an substituted or unsubstituted heterocyclic ring;each instance of R^(D3) is independently hydrogen, halogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(D3a), —N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a),—CH₂N(R^(D3a))₂, —CH₂SR^(D3a), —C(═O)R^(D3a), —C(═O)OR^(D3a),—C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂, —C(═S)R^(D3a), —C(═S)OR^(D3a),—C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂, —C(═NR^(D3a))R^(D3a),—C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring; R^(D4) is a leavinggroup selected from the group consisting of —Br, —Cl, —I, and—OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each instance of X¹ isindependently a bond, —C(═O)—, —SO₂—, —NR^(D5)—, optionally substitutedalkylene, or optionally substituted heteroarylene, wherein R^(D5) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; each instance of Yis independently O, S, or NR^(D6), wherein R^(D6) is hydrogen, C₁₋₆alkyl, or a nitrogen protecting group; and each instance of z and z₁ isindependently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
 3. A compoundof Formula (III):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof; wherein: Ring A is aryl, arylalkenyl, or heteroaryl;each instance of R^(A) is independently selected from the groupconsisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A1), —N(R^(A1))₂, —SR^(A1), —CN, —C(═NR^(A1))R^(A1),—C(═NR^(A1))OR^(A1), —C(═NR^(A1))SR^(A1), —C(═NR^(A1))N(R^(A1))₂,—C(═O)NR^(A1)—, —NR^(A1)C(═O)—, —C(═O)R^(A1), —C(═S)R^(A1),—C(═S)OR^(A1), —C(═S)SR^(A1), —C(═S)N(R^(A1))₂, —NO₂, —N₃,—N(R^(A1))₃+F—, —N(R^(A1))₃ ⁺Cl⁻, —N(R^(A1))₃ ⁺Br⁻, —N(R^(A1))₃ ⁺I⁻,—N(OR^(A1))R^(A1), —NR^(A1)C(═O)R^(A1), —NR^(A1)C(═O)OR^(A1),—NR^(A1)C(═O)SR^(A1), —NR^(A1)C(═O)N(R^(A1))₂, —NR^(A1)C(═S)R^(A1),—NR^(A1)C(═S)OR^(A1), —NR^(A1)C(═S)SR^(A1), —NR^(A1)C(═S)N(R^(A1))₂,—NR^(A1)C(═NR^(A1))R^(A1), —NR^(A1)C(═NR^(A1))OR^(A1),—NR^(A1)C(═NR^(A1))SR^(A1), —NR^(A1)C(═NR^(A1))N(R^(A1))₂,—NR^(A1)S(═O)₂R^(A1), —NR^(A1)S(═O)₂OR^(A1), —NR^(A1)S(═O)₂SR^(A1),—NR^(A1)S(═O)₂N(R^(A1))₂, —NR^(A1)S(═O)R^(A1), —NR^(A1)S(═O)OR^(A1),—NR^(A1)S(═O)SR^(A1), —NR^(A1)S(═O)N(R^(A1))₂, —NR^(A1)P(═O),—NR^(A1)P(═O)₂, —NR^(A1)P(═O)(R^(A1))₂, —NR^(A1)P(═O)R^(A1)(OR^(A1)),—NR^(A1)P(═O)(OR^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —OC(═NR^(A1))R^(A1), —OC(═NR^(A1))OR^(A1),—OC(═NR^(A1))N(R^(A1))₂, —OC(═S)R^(A1), —OC(═S)OR^(A1), —OC(═S)SR^(A1),—OC(═S)N(R^(A1))₂, —ON(R^(A1))₂, —OS(═O)R^(A1), —OS(═O)OR^(A1),—OS(═O)SR^(A1), —OS(═O)N(R^(A1))₂, —OS(═O)₂R^(A1), —OS(═O)₂OR^(A1),—OS(═O)₂SR^(A1), —OS(═O)₂N(R^(A1))₂, —OP(═O)₂, —OP(═O)(R^(A1))₂,—OP(═O)R^(A1)(OR^(A1)), —OP(═O)(OR^(A1))₂, —OP(═O), —OP(R^(A1))₂,—OPR^(A1)(OR^(A1)), —OP(OR^(A1))₂, —OSi(R^(A1))₃, —OSi(R^(A1))₂OR^(A1),—OSi(R^(A1))(OR^(A1))₂, —OSi(OR^(A1))₃, —SSR^(A1), —S(═O)R^(A1),—S(═O)OR^(A1), —S(═O)N(R^(A1))₂, —S(═O)₂R^(A1), —S(═O)₂OR^(A),—S(═O)₂N(R^(A1))₂, —SC(═O)R^(A1), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —SC(═S)R^(A1), —SC(═S)OR^(A1), —SC(═S)SR^(A1),—SC(═S)N(R^(A1))₂, —P(R^(A1))₂, —PR^(A1)(OR^(A1)), —P(OR^(A1))₂, —P(═O),—P(═O)(R^(A1))₂, —P(═O)(OR^(A1))₂, —P(═O)R^(A1)(OR^(A1)), —P(═O)₂,—B(R^(A1))₂, —B(OR^(A1))₂, —BR^(A1)(OR^(A1)), —Si(R^(A1))₃,—Si(R^(A1))₂OR^(A1), —SiR^(A1)(OR^(A1))₂, and —Si(OR^(A1))₃, whereineach occurrence of R^(A1) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(A1) groups are joined to form an optionally substituted heterocyclicring; k is 0, 1, 2, 3, 4, or 5; Ring C is a carbocyclic, heterocyclic,aryl, or heteroaryl ring; each instance of R^(C) is independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(C1), —N(R^(C1))₂, —SR^(C1), —CN,—C(═NR^(C1))R^(C1), —C(═NR^(C1))OR^(q), —C(═NR^(C1))SR^(C1),—C(═NR^(C1))N(R^(C1))₂, —C(═O)R^(C1), —C(═S)R^(C1), —C(═S)OR^(C1),—C(═S)SR^(C1), —C(═S)N(R^(C1))₂, —NO₂, —N₃, —N(R^(C1))₃ ⁺F⁻, —N(R^(C1))₃⁺Cl⁻, —N(R^(C1))₃ ⁺Br⁻, —N(R^(C1))₃ ⁺I⁻, —N(OR^(C1))R^(C1),—NR^(C1)C(═O)R^(C1), —NR^(C1)C(═O)OR^(C1), —NR^(C1)C(═O)SR^(C1),—NR^(C1)C(═O)N(R^(C1))₂, —NR^(C1)C(═S)R^(C1), —NR^(C1)C(═S)OR^(C1),—NR^(C1)C(═S)SR^(C1), —NR^(C1)C(═S)N(R^(C1))₂, —NR^(C1)C(═NR)R^(C1),—NR^(C1)C(═NR^(C1))OR^(C1), —NR^(C1)C(═NR^(C1))SR^(C1),—NR^(C1)C(═NR^(C1))N(R^(C1))₂, —NR^(C1)S(═O)₂R^(C1),—NR^(C1)S(═O)₂OR^(C1), —NR^(C1)S(═O)₂SR^(C1), —NR^(C1)S(═O)₂N(R^(C1))₂,—NR^(C1)S(═O)R^(C1), —NR^(C1)S(═O)OR^(C1), —NR^(C1)S(═O)SR^(C1),—NR^(C1)S(═O)N(R^(C1))₂, —NR^(C1)P(═O), —NR^(C1)P(═O)₂,—NR^(C1)P(═O)(R^(C1))₂, —NR^(C1)P(═O)R^(C1)(OR^(C1)),—NR^(C1)P(═O)(OR^(C1))₂, —OC(═O)R^(C1), —OC(═O)OR^(C1), —OC(═O)SR^(C1),—OC(═O)N(R^(C1))₂, —OC(═NR^(C1))R^(C1), —OC(═NR^(C1))OR^(C1),—OC(═NR^(C1))N(R^(C1))₂, —OC(═S)R^(C1), —OC(═S)OR^(C1), —OC(═S)SR^(C1),—OC(═S)N(R^(C1))₂, —ON(R^(C1))₂, —OS(═O)R^(C1), —OS(═O)OR^(C1),—OS(═O)SR^(C1), —OS(═O)N(R^(C1))₂, —OS(═O)₂R^(C1), —OS(═O)₂OR^(C1),—OS(═O)₂SR^(C1), —OS(═O)₂N(R^(C1))₂, —OP(═O)₂, —OP(═O)(R^(C1))₂,—OP(═O)R^(C1)(OR^(C1)), —OP(═O)(OR^(C1))₂, —OP(═O), —OP(R^(C1))₂,—OPR^(C1)(OR^(C1)), —OP(OR^(C1))₂, —OSi(R^(C1))₃, —OSi(R^(C1))₂OR^(C1),—OSi(R^(C1))(OR^(C1))₂, —OSi(OR^(C1))₃, —SSR^(C1), —S(═O)R^(C1),—S(═O)OR^(C1), —S(═O)N(R^(C1))₂, —S(═O)₂R^(C1), —S(═O)₂OR^(C1),—S(═O)₂N(R^(C1))₂, —SC(═O)R^(C1), —SC(═O)OR^(C1), —SC(═O)SR^(C1),—SC(═O)N(R^(C1))₂, —SC(═S)R^(C1), —SC(═S)OR^(C1), —SC(═S)SR^(C1),—SC(═S)N(R^(C1))₂, —P(R^(C1))₂, —PR^(C1)(OR^(C1)), —P(OR^(C1))₂, —P(═O),—P(═O)(R^(C1))₂, —P(═O)(OR^(C1))₂, —P(═O)R^(C1)(OR^(C1)), —P(═O)₂,—B(R^(C1))₂, —B(OR^(C1))₂, —BR^(C1)(OR^(C1)), —Si(R^(C1))₃,—Si(R^(C1))₂OR^(C1), —SiR^(C1)(OR^(C1))₂, and —Si(OR^(C1))₃, whereineach occurrence of R^(C1) is independently selected from the groupconsisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, a sulfur protecting group when attached to a sulfur atom, or twoR^(C1) groups are joined to form an optionally substituted heterocyclicring or optionally substituted heteroaryl ring; R^(q) is independentlyhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, or a nitrogen protecting group;n is 0, 1, 2, 3, or 4; L is a bond or an optionally substituted,branched or unbranched C₁₋₆ hydrocarbon chain; R^(D) is any one ofFormulae (i-1)-(i-43):

wherein: each instance of R^(D1) is independently hydrogen, halogen,acyl, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —CN, —NO₂, —OR^(D1a), —N(R^(D1a))₂, —SR^(D1a), —CH₂OR^(D1a),—CH₂N(R^(D1a))₂, —CH₂SR^(D1a), —C(═O)R^(D1a), —C(═O)OR^(D1a),—C(═O)SR^(D1a), —C(═O)N(R^(D1a))₂, —C(═S)R^(D1a), —C(═S)OR^(D1a),—C(═S)SR^(D1a), —C(═S)N(R^(D1a))₂, —C(═NR^(D1a))R^(D1a),—C(═NR^(D1a))OR^(D1a) C(═NR^(D1a))SR^(D1a), or —C(═NR^(D1a))N(R^(D1a))₂,wherein each occurrence of R^(D1a) is independently hydrogen, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, or two R^(D1a) groups are joined to form an substituted orunsubstituted heterocyclic ring; each instance of R^(D2) isindependently hydrogen, halogen, acyl, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —CN, —NO₂, —OR^(D2a),—N(R^(D2a))₂, —SR^(D2a), —CH₂OR^(D2a)CH₂N(R^(D2a))₂, —CH₂SR^(D2a),—C(═O)R^(D2a), —C(═O)OR^(D2a), —C(═O)SR^(D2a), —C(═O)N(R^(D2a))₂,—C(═S)R^(D2a), —C(═S)OR^(D2a), —C(═S)SR^(D2a), —C(═S)N(R^(D2a))₂,—C(═NR^(D2a))R^(D2a), —C(═NR^(D2a))OR^(D2a), —C(═NR^(D2a))SR^(D2a), and—C(═NR^(D2a))N(R^(D2a))₂, wherein each occurrence of R^(D2a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl, or two R^(D2a) groups arejoined to form an substituted or unsubstituted heterocyclic ring; eachinstance of R^(D3) is independently hydrogen, halogen, acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR^(D3a),—N(R^(D3a))₂, —SR^(D3a), —CH₂OR^(D3a), —CH₂N(R^(D3a))₂, —CH₂SR^(D3a),—C(═O)R^(D3a), —C(═O)OR^(D3a), —C(═O)SR^(D3a), —C(═O)N(R^(D3a))₂,—C(═S)R^(D3a), —C(═S)OR^(D3a), —C(═S)SR^(D3a), —C(═S)N(R^(D3a))₂,—C(═NR^(D3a))R^(D3a), —C(═NR^(D3a))OR^(D3a), —C(═NR^(D3a))SR^(D3a), or—C(═NR^(D3a))N(R^(D3a))₂ wherein each occurrence of R^(D3a) isindependently hydrogen, acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, or two R^(D3a) groups arejoined to form an substituted or unsubstituted heterocyclic ring;optionally R^(D1) and R^(D3), or R^(D2) and R^(D3), or R^(D1) and R^(D2)are joined to form an substituted or unsubstituted carbocyclic orsubstituted or unsubstituted heterocyclic ring; R^(D4) is a leavinggroup selected from the group consisting of —Br, —Cl, —I, and—OS(═O)_(w)R^(D4a), wherein w is 1 or 2, and R^(D4a) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each instance of X¹ isindependently a bond, —C(═O)—, —SO₂—, —NR^(D5)—, optionally substitutedalkylene, or optionally substituted heteroarylene, wherein R^(D5) ishydrogen, C₁₋₆ alkyl, or a nitrogen protecting group; each instance of Yis independently O, S, or NR^(D6), wherein R^(D6) is hydrogen, C₁₋₆alkyl, or a nitrogen protecting group; and each instance of z and z₁ isindependently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
 4. (canceled)5. The compound of claim 1, wherein Ring A is a 5-membered or6-membered, monocyclic heteroaryl ring.
 6. The compound of claim 5,wherein

is of formula:


7. (canceled)
 8. The compound of claim 5, wherein

is of formula:


9. (canceled)
 10. The compound of claim 1, wherein

is one of the following formulae:

11-12. (canceled)
 13. The compound of claim 1, wherein Ring C is aryl.14. (canceled)
 15. The compound of claim 1, wherein Ring C is indoline.16. (canceled)
 17. The compound of claim 1, wherein L is a bond or—CH₂—.
 18. (canceled)
 19. The compound of claim 1, wherein R^(D) is offormula:


20. (canceled)
 21. The compound of claim 1, wherein R^(D) is of formula:

22-25. (canceled)
 26. The compound of claim 1, wherein the compound isof formula:

or a pharmaceutically acceptable salt thereof. 27-31. (canceled)
 32. Thecompound of claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof. 33-41. (canceled)
 42. Thecompound of claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof. 43-48. (canceled)
 49. Apharmaceutical composition comprising a therapeutically orprophylactically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof, and optionally a pharmaceutically acceptable excipient.50. A method of treating or preventing an infectious disease in asubject suffering therefrom, the method comprising: administering to thesubject a therapeutically or prophylactically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug thereof. 51-58. (canceled)
 59. A methodof preventing a viral infection in a subject who was or may be exposedto a virus, the method comprising: administering to the subject aprophylactically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof. 60-69. (canceled)
 70. A kit for treating or preventingan infectious disease, the kit comprising: a first container comprisinga compound of claim 1, or a pharmaceutically acceptable salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug thereof; and instructions foradministering the compound, or a pharmaceutically acceptable salt,solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, or prodrug thereof, to a subject totreat or prevent the infectious disease.
 71. The compound of claim 1,wherein the compound is of the formula:

or a pharmaceutically acceptable salt thereof.